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Open Access 06-07-2024 | Type 2 Diabetes | CE-REVIEW

Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies

Authors: Patrycja Jakubek, Barbara Pakula, Martin Rossmeisl, Paolo Pinton, Alessandro Rimessi, Mariusz Roman Wieckowski

Published in: Internal and Emergency Medicine

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Abstract

Autophagy is an evolutionarily conserved process that plays a pivotal role in the maintenance of cellular homeostasis and its impairment has been implicated in the pathogenesis of various metabolic diseases including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review synthesizes the current evidence from human studies on autophagy alterations under these metabolic conditions. In obesity, most data point to autophagy upregulation during the initiation phase of autophagosome formation, potentially in response to proinflammatory conditions in the adipose tissue. Autophagosome formation appears to be enhanced under hyperglycemic or insulin-resistant conditions in patients with T2D, possibly acting as a compensatory mechanism to eliminate damaged organelles and proteins. Other studies have proposed that prolonged hyperglycemia and disrupted insulin signaling hinder autophagic flux, resulting in the accumulation of dysfunctional cellular components that can contribute to β-cell dysfunction. Evidence from patients with MASLD supports autophagy inhibition in disease progression. Nevertheless, given the available data, it is difficult to ascertain whether autophagy is enhanced or suppressed in these conditions because the levels of autophagy markers depend on the overall metabolism of specific organs, tissues, experimental conditions, or disease duration. Owing to these constraints, determining whether the observed shifts in autophagic activity precede or result from metabolic diseases remains challenging. Additionally, autophagy-modulating strategies are shortly discussed. To conclude, more studies investigating autophagy impairment are required to gain a more comprehensive understanding of its role in the pathogenesis of obesity, T2D, and MASLD and to unveil novel therapeutic strategies for these conditions.
Literature
1.
go back to reference Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, Swain MG, Congly SE, Kaplan GG, Shaheen AA (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 7:851–861PubMedCrossRef Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, Swain MG, Congly SE, Kaplan GG, Shaheen AA (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 7:851–861PubMedCrossRef
2.
go back to reference Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PALu, Ma Y, Mainoo J, Mensah NK, Merriman GA, Mokdad TR, Moschandreas AH, Naghavi J, Naheed M, Nand A, Narayan D, Nelson KM, Neuhouser EL, Nisar ML, Ohkubo MI, Oti T, Pedroza SO et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781PubMedPubMedCentralCrossRef Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PALu, Ma Y, Mainoo J, Mensah NK, Merriman GA, Mokdad TR, Moschandreas AH, Naghavi J, Naheed M, Nand A, Narayan D, Nelson KM, Neuhouser EL, Nisar ML, Ohkubo MI, Oti T, Pedroza SO et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781PubMedPubMedCentralCrossRef
3.
go back to reference Collaborators GBDD (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402:203–234CrossRef Collaborators GBDD (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402:203–234CrossRef
4.
go back to reference Boutari C, Mantzoros CS (2022) A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133:155217PubMedPubMedCentralCrossRef Boutari C, Mantzoros CS (2022) A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133:155217PubMedPubMedCentralCrossRef
5.
go back to reference Organization, W. H. (2022) WHO European Regional Obesity Report 2022 Organization, W. H. (2022) WHO European Regional Obesity Report 2022
6.
go back to reference Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ (2022) IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 183:109119PubMedCrossRef Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ (2022) IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 183:109119PubMedCrossRef
7.
go back to reference Lee YH, Cho Y, Lee BW, Park CY, Lee DH, Cha BS, Rhee EJ (2019) Nonalcoholic fatty liver disease in diabetes. Part I: epidemiology and diagnosis. Diabetes Metab J 43:31–45PubMedCrossRef Lee YH, Cho Y, Lee BW, Park CY, Lee DH, Cha BS, Rhee EJ (2019) Nonalcoholic fatty liver disease in diabetes. Part I: epidemiology and diagnosis. Diabetes Metab J 43:31–45PubMedCrossRef
8.
go back to reference Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84PubMedCrossRef Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84PubMedCrossRef
9.
go back to reference Loomba R, Friedman SL, Shulman GI (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184:2537–2564PubMedCrossRef Loomba R, Friedman SL, Shulman GI (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184:2537–2564PubMedCrossRef
10.
go back to reference Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, Salom C, Jover A, Mora V, Roldan I, Sola E, Rocha M, Victor VM (2019) Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med 8:1385PubMedPubMedCentralCrossRef Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, Salom C, Jover A, Mora V, Roldan I, Sola E, Rocha M, Victor VM (2019) Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med 8:1385PubMedPubMedCentralCrossRef
12.
go back to reference Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cadwell K, Cecconi F, Choi AMK, Choi ME, Chu CT, Codogno P, Colombo MI, Cuervo AM, Deretic V, Dikic I, Elazar Z, Eskelinen EL, Fimia GM, Gewirtz DA, Green DR, Hansen M, Jaattela M, Johansen T, Juhasz G, Karantza V, Kraft C, Kroemer G, Ktistakis NT, Kumar S, Lopez-Otin C, Macleod KF, Madeo F, Martinez J, Melendez A, Mizushima N, Munz C, Penninger JM, Perera RM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Sadoshima J, Santambrogio L, Scorrano L, Simon HU, Simon AK, Simonsen A, Stolz A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Galluzzi L, Pietrocola F (2021) Autophagy in major human diseases. EMBO J 40:e108863PubMedPubMedCentralCrossRef Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cadwell K, Cecconi F, Choi AMK, Choi ME, Chu CT, Codogno P, Colombo MI, Cuervo AM, Deretic V, Dikic I, Elazar Z, Eskelinen EL, Fimia GM, Gewirtz DA, Green DR, Hansen M, Jaattela M, Johansen T, Juhasz G, Karantza V, Kraft C, Kroemer G, Ktistakis NT, Kumar S, Lopez-Otin C, Macleod KF, Madeo F, Martinez J, Melendez A, Mizushima N, Munz C, Penninger JM, Perera RM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Sadoshima J, Santambrogio L, Scorrano L, Simon HU, Simon AK, Simonsen A, Stolz A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Galluzzi L, Pietrocola F (2021) Autophagy in major human diseases. EMBO J 40:e108863PubMedPubMedCentralCrossRef
14.
15.
go back to reference Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552PubMedCrossRef Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552PubMedCrossRef
17.
go back to reference Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14:207–215PubMedCrossRef Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14:207–215PubMedCrossRef
19.
go back to reference Cao W, Li J, Yang K, Cao D (2021) An overview of autophagy: mechanism, regulation and research progress. Bull Cancer 108:304–322PubMedCrossRef Cao W, Li J, Yang K, Cao D (2021) An overview of autophagy: mechanism, regulation and research progress. Bull Cancer 108:304–322PubMedCrossRef
20.
go back to reference Tabibzadeh S (2023) Role of autophagy in aging: the good, the bad, and the ugly. Aging Cell 22:e13753PubMedCrossRef Tabibzadeh S (2023) Role of autophagy in aging: the good, the bad, and the ugly. Aging Cell 22:e13753PubMedCrossRef
23.
go back to reference Mulcahy Levy JM, Thorburn A (2020) Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27:843–857PubMedCrossRef Mulcahy Levy JM, Thorburn A (2020) Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27:843–857PubMedCrossRef
24.
25.
go back to reference Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871PubMedCrossRef Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871PubMedCrossRef
26.
go back to reference Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34:620–627PubMedCrossRef Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34:620–627PubMedCrossRef
28.
go back to reference Zhou B, Kreuzer J, Kumsta C, Wu L, Kamer KJ, Cedillo L, Zhang Y, Li S, Kacergis MC, Webster CM, Fejes-Toth G, Naray-Fejes-Toth A, Das S, Hansen M, Haas W, Soukas AA (2019) Mitochondrial permeability uncouples elevated autophagy and lifespan extension. Cell 177(299–314):e16 Zhou B, Kreuzer J, Kumsta C, Wu L, Kamer KJ, Cedillo L, Zhang Y, Li S, Kacergis MC, Webster CM, Fejes-Toth G, Naray-Fejes-Toth A, Das S, Hansen M, Haas W, Soukas AA (2019) Mitochondrial permeability uncouples elevated autophagy and lifespan extension. Cell 177(299–314):e16
29.
go back to reference Aspernig H, Heimbucher T, Qi W, Gangurde D, Curic S, Yan Y, Donner von Gromoff E, Baumeister R, Thien A (2019) Mitochondrial perturbations couple mTORC2 to autophagy in C. elegans. Cell Rep 29:1399-1409.e5PubMedCrossRef Aspernig H, Heimbucher T, Qi W, Gangurde D, Curic S, Yan Y, Donner von Gromoff E, Baumeister R, Thien A (2019) Mitochondrial perturbations couple mTORC2 to autophagy in C. elegans. Cell Rep 29:1399-1409.e5PubMedCrossRef
30.
31.
go back to reference Holczer M, Hajdu B, Lorincz T, Szarka A, Banhegyi G, Kapuy O (2020) Fine-tuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation. Sci Rep 10:17803PubMedPubMedCentralCrossRef Holczer M, Hajdu B, Lorincz T, Szarka A, Banhegyi G, Kapuy O (2020) Fine-tuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation. Sci Rep 10:17803PubMedPubMedCentralCrossRef
32.
go back to reference Sun K, Deng W, Zhang S, Cai N, Jiao S, Song J, Wei L (2013) Paradoxical roles of autophagy in different stages of tumorigenesis: protector for normal or cancer cells. Cell Biosci 3:35PubMedPubMedCentralCrossRef Sun K, Deng W, Zhang S, Cai N, Jiao S, Song J, Wei L (2013) Paradoxical roles of autophagy in different stages of tumorigenesis: protector for normal or cancer cells. Cell Biosci 3:35PubMedPubMedCentralCrossRef
33.
go back to reference Noda T, Fujita N, Yoshimori T (2009) The late stages of autophagy: how does the end begin? Cell Death Differ 16:984–990PubMedCrossRef Noda T, Fujita N, Yoshimori T (2009) The late stages of autophagy: how does the end begin? Cell Death Differ 16:984–990PubMedCrossRef
34.
go back to reference Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA (2014) WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell 55:238–252PubMedPubMedCentralCrossRef Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA (2014) WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell 55:238–252PubMedPubMedCentralCrossRef
35.
go back to reference Rojano A, Sena E, Manzano-Nunez R, Pericas JM, Ciudin A (2023) NAFLD as the metabolic hallmark of obesity. Intern Emerg Med 18:31–41PubMedCrossRef Rojano A, Sena E, Manzano-Nunez R, Pericas JM, Ciudin A (2023) NAFLD as the metabolic hallmark of obesity. Intern Emerg Med 18:31–41PubMedCrossRef
36.
go back to reference Zhang Y, Sowers JR, Ren J (2018) Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol 14:356–376PubMedCrossRef Zhang Y, Sowers JR, Ren J (2018) Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol 14:356–376PubMedCrossRef
37.
38.
go back to reference Ost A, Svensson K, Ruishalme I, Brannmark C, Franck N, Krook H, Sandstrom P, Kjolhede P, Stralfors P (2010) Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med 16:235–246PubMedPubMedCentralCrossRef Ost A, Svensson K, Ruishalme I, Brannmark C, Franck N, Krook H, Sandstrom P, Kjolhede P, Stralfors P (2010) Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med 16:235–246PubMedPubMedCentralCrossRef
39.
go back to reference Kovsan J, Bluher M, Tarnovscki T, Kloting N, Kirshtein B, Madar L, Shai I, Golan R, Harman-Boehm I, Schon MR, Greenberg AS, Elazar Z, Bashan N, Rudich A (2011) Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab 96:E268–E277PubMedCrossRef Kovsan J, Bluher M, Tarnovscki T, Kloting N, Kirshtein B, Madar L, Shai I, Golan R, Harman-Boehm I, Schon MR, Greenberg AS, Elazar Z, Bashan N, Rudich A (2011) Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab 96:E268–E277PubMedCrossRef
40.
go back to reference Nunez CE, Rodrigues VS, Gomes FS, Moura RF, Victorio SC, Bombassaro B, Chaim EA, Pareja JC, Geloneze B, Velloso LA, Araujo EP (2013) Defective regulation of adipose tissue autophagy in obesity. Int J Obes 37:1473–1480CrossRef Nunez CE, Rodrigues VS, Gomes FS, Moura RF, Victorio SC, Bombassaro B, Chaim EA, Pareja JC, Geloneze B, Velloso LA, Araujo EP (2013) Defective regulation of adipose tissue autophagy in obesity. Int J Obes 37:1473–1480CrossRef
41.
go back to reference Kosacka J, Kern M, Kloting N, Paeschke S, Rudich A, Haim Y, Gericke M, Serke H, Stumvoll M, Bechmann I, Nowicki M, Bluher M (2015) Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol 409:21–32PubMedCrossRef Kosacka J, Kern M, Kloting N, Paeschke S, Rudich A, Haim Y, Gericke M, Serke H, Stumvoll M, Bechmann I, Nowicki M, Bluher M (2015) Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol 409:21–32PubMedCrossRef
42.
go back to reference Xu Q, Mariman ECM, Roumans NJT, Vink RG, Goossens GH, Blaak EE, Jocken JWE (2018) Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity. Adipocyte 7:12–19PubMedPubMedCentralCrossRef Xu Q, Mariman ECM, Roumans NJT, Vink RG, Goossens GH, Blaak EE, Jocken JWE (2018) Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity. Adipocyte 7:12–19PubMedPubMedCentralCrossRef
43.
go back to reference Rodriguez A, Gomez-Ambrosi J, Catalan V, Rotellar F, Valenti V, Silva C, Mugueta C, Pulido MR, Vazquez R, Salvador J, Malagon MM, Colina I, Fruhbeck G (2012) The ghrelin O-acyltransferase-ghrelin system reduces TNF-alpha-induced apoptosis and autophagy in human visceral adipocytes. Diabetologia 55:3038–3050PubMedCrossRef Rodriguez A, Gomez-Ambrosi J, Catalan V, Rotellar F, Valenti V, Silva C, Mugueta C, Pulido MR, Vazquez R, Salvador J, Malagon MM, Colina I, Fruhbeck G (2012) The ghrelin O-acyltransferase-ghrelin system reduces TNF-alpha-induced apoptosis and autophagy in human visceral adipocytes. Diabetologia 55:3038–3050PubMedCrossRef
44.
go back to reference Jansen HJ, van Essen P, Koenen T, Joosten LA, Netea MG, Tack CJ, Stienstra R (2012) Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153:5866–5874PubMedCrossRef Jansen HJ, van Essen P, Koenen T, Joosten LA, Netea MG, Tack CJ, Stienstra R (2012) Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153:5866–5874PubMedCrossRef
45.
go back to reference Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M, Rouault C, Clement K, Dugail I (2015) DAPK2 downregulation associates with attenuated adipocyte autophagic clearance in human obesity. Diabetes 64:3452–3463PubMedCrossRef Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M, Rouault C, Clement K, Dugail I (2015) DAPK2 downregulation associates with attenuated adipocyte autophagic clearance in human obesity. Diabetes 64:3452–3463PubMedCrossRef
46.
go back to reference Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre-Millo M, Poitou C, Basdevant A, Stich V, Viguerie N, Langin D, Bedossa P, Zucker JD, Clement K (2008) Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 9:R14PubMedPubMedCentralCrossRef Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre-Millo M, Poitou C, Basdevant A, Stich V, Viguerie N, Langin D, Bedossa P, Zucker JD, Clement K (2008) Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 9:R14PubMedPubMedCentralCrossRef
47.
go back to reference Haim Y, Bluher M, Slutsky N, Goldstein N, Kloting N, Harman-Boehm I, Kirshtein B, Ginsberg D, Gericke M, Guiu Jurado E, Kovsan J, Tarnovscki T, Kachko L, Bashan N, Gepner Y, Shai I, Rudich A (2015) Elevated autophagy gene expression in adipose tissue of obese humans: a potential non-cell-cycle-dependent function of E2F1. Autophagy 11:2074–2088PubMedPubMedCentralCrossRef Haim Y, Bluher M, Slutsky N, Goldstein N, Kloting N, Harman-Boehm I, Kirshtein B, Ginsberg D, Gericke M, Guiu Jurado E, Kovsan J, Tarnovscki T, Kachko L, Bashan N, Gepner Y, Shai I, Rudich A (2015) Elevated autophagy gene expression in adipose tissue of obese humans: a potential non-cell-cycle-dependent function of E2F1. Autophagy 11:2074–2088PubMedPubMedCentralCrossRef
48.
go back to reference Cheng AYY, Gomes MB, Kalra S, Kengne AP, Mathieu C, Shaw JE (2023) Applying the WHO global targets for diabetes mellitus. Nat Rev Endocrinol 19:194–200PubMedCrossRef Cheng AYY, Gomes MB, Kalra S, Kengne AP, Mathieu C, Shaw JE (2023) Applying the WHO global targets for diabetes mellitus. Nat Rev Endocrinol 19:194–200PubMedCrossRef
49.
50.
go back to reference Barutta F, Bellini S, Kimura S, Hase K, Corbetta B, Corbelli A, Fiordaliso F, Bruno S, Biancone L, Barreca A, Papotti MG, Hirsh E, Martini M, Gambino R, Durazzo M, Ohno H, Gruden G (2023) Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy. Autophagy 19:505–524PubMedCrossRef Barutta F, Bellini S, Kimura S, Hase K, Corbetta B, Corbelli A, Fiordaliso F, Bruno S, Biancone L, Barreca A, Papotti MG, Hirsh E, Martini M, Gambino R, Durazzo M, Ohno H, Gruden G (2023) Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy. Autophagy 19:505–524PubMedCrossRef
51.
go back to reference Barlow AD, Thomas DC (2015) Autophagy in diabetes: beta-cell dysfunction, insulin resistance, and complications. DNA Cell Biol 34:252–260PubMedCrossRef Barlow AD, Thomas DC (2015) Autophagy in diabetes: beta-cell dysfunction, insulin resistance, and complications. DNA Cell Biol 34:252–260PubMedCrossRef
52.
go back to reference Moller AB, Kampmann U, Hedegaard J, Thorsen K, Nordentoft I, Vendelbo MH, Moller N, Jessen N (2017) Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes. Sci Rep 7:43775PubMedPubMedCentralCrossRef Moller AB, Kampmann U, Hedegaard J, Thorsen K, Nordentoft I, Vendelbo MH, Moller N, Jessen N (2017) Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes. Sci Rep 7:43775PubMedPubMedCentralCrossRef
53.
go back to reference Kruse R, Vind BF, Petersson SJ, Kristensen JM, Hojlund K (2015) Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes. Diabetologia 58:2087–2095PubMedCrossRef Kruse R, Vind BF, Petersson SJ, Kristensen JM, Hojlund K (2015) Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes. Diabetologia 58:2087–2095PubMedCrossRef
54.
go back to reference Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52:1083–1086PubMedCrossRef Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52:1083–1086PubMedCrossRef
55.
go back to reference Mizukami H, Takahashi K, Inaba W, Tsuboi K, Osonoi S, Yoshida T, Yagihashi S (2014) Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of beta-cell mass in Japanese type 2 diabetic patients. Diabetes Care 37:1966–1974PubMedCrossRef Mizukami H, Takahashi K, Inaba W, Tsuboi K, Osonoi S, Yoshida T, Yagihashi S (2014) Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of beta-cell mass in Japanese type 2 diabetic patients. Diabetes Care 37:1966–1974PubMedCrossRef
56.
go back to reference Riahi Y, Wikstrom JD, Bachar-Wikstrom E, Polin N, Zucker H, Lee MS, Quan W, Haataja L, Liu M, Arvan P, Cerasi E, Leibowitz G (2016) Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia 59:1480–1491PubMedPubMedCentralCrossRef Riahi Y, Wikstrom JD, Bachar-Wikstrom E, Polin N, Zucker H, Lee MS, Quan W, Haataja L, Liu M, Arvan P, Cerasi E, Leibowitz G (2016) Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia 59:1480–1491PubMedPubMedCentralCrossRef
57.
go back to reference Lee MS (2014) Role of islet beta cell autophagy in the pathogenesis of diabetes. Trends Endocrinol Metab 25:620–627PubMedCrossRef Lee MS (2014) Role of islet beta cell autophagy in the pathogenesis of diabetes. Trends Endocrinol Metab 25:620–627PubMedCrossRef
58.
go back to reference Liang R, Liu N, Cao J, Liu T, Sun P, Cai X, Zhang L, Liu Y, Zou J, Wang L, Ding X, Zhang B, Shen Z, Yoshida S, Dou J, Wang S (2022) HIF-1alpha/FOXO1 axis regulated autophagy is protective for beta cell survival under hypoxia in human islets. Biochim Biophys Acta Mol Basis Dis 1868:166356PubMedCrossRef Liang R, Liu N, Cao J, Liu T, Sun P, Cai X, Zhang L, Liu Y, Zou J, Wang L, Ding X, Zhang B, Shen Z, Yoshida S, Dou J, Wang S (2022) HIF-1alpha/FOXO1 axis regulated autophagy is protective for beta cell survival under hypoxia in human islets. Biochim Biophys Acta Mol Basis Dis 1868:166356PubMedCrossRef
59.
go back to reference Alizadeh S, Mazloom H, Sadeghi A, Emamgholipour S, Golestani A, Noorbakhsh F, Khoshniatnikoo M, Meshkani R (2018) Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients. J Physiol Biochem 74:369–379PubMedCrossRef Alizadeh S, Mazloom H, Sadeghi A, Emamgholipour S, Golestani A, Noorbakhsh F, Khoshniatnikoo M, Meshkani R (2018) Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients. J Physiol Biochem 74:369–379PubMedCrossRef
60.
go back to reference Rovira-Llopis S, Diaz-Morales N, Banuls C, Blas-Garcia A, Polo M, Lopez-Domenech S, Jover A, Rocha M, Hernandez-Mijares A, Victor VM (2015) Is autophagy altered in the leukocytes of type 2 diabetic patients? Antioxid Redox Signal 23:1050–1056PubMedCrossRef Rovira-Llopis S, Diaz-Morales N, Banuls C, Blas-Garcia A, Polo M, Lopez-Domenech S, Jover A, Rocha M, Hernandez-Mijares A, Victor VM (2015) Is autophagy altered in the leukocytes of type 2 diabetic patients? Antioxid Redox Signal 23:1050–1056PubMedCrossRef
62.
63.
go back to reference Muriach M, Flores-Bellver M, Romero FJ, Barcia JM (2014) Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014:102158PubMedPubMedCentralCrossRef Muriach M, Flores-Bellver M, Romero FJ, Barcia JM (2014) Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014:102158PubMedPubMedCentralCrossRef
64.
go back to reference Kanamori H, Naruse G, Yoshida A, Minatoguchi S, Watanabe T, Kawaguchi T, Tanaka T, Yamada Y, Takasugi H, Mikami A, Minatoguchi S, Miyazaki T, Okura H (2021) Morphological characteristics in diabetic cardiomyopathy associated with autophagy. J Cardiol 77:30–40PubMedCrossRef Kanamori H, Naruse G, Yoshida A, Minatoguchi S, Watanabe T, Kawaguchi T, Tanaka T, Yamada Y, Takasugi H, Mikami A, Minatoguchi S, Miyazaki T, Okura H (2021) Morphological characteristics in diabetic cardiomyopathy associated with autophagy. J Cardiol 77:30–40PubMedCrossRef
65.
66.
go back to reference Fetterman JL, Holbrook M, Flint N, Feng B, Breton-Romero R, Linder EA, Berk BD, Duess MA, Farb MG, Gokce N, Shirihai OS, Hamburg NM, Vita JA (2016) Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis 247:207–217PubMedPubMedCentralCrossRef Fetterman JL, Holbrook M, Flint N, Feng B, Breton-Romero R, Linder EA, Berk BD, Duess MA, Farb MG, Gokce N, Shirihai OS, Hamburg NM, Vita JA (2016) Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis 247:207–217PubMedPubMedCentralCrossRef
67.
go back to reference Munasinghe PE, Riu F, Dixit P, Edamatsu M, Saxena P, Hamer NS, Galvin IF, Bunton RW, Lequeux S, Jones G, Lamberts RR, Emanueli C, Madeddu P, Katare R (2016) Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway. Int J Cardiol 202:13–20PubMedCrossRef Munasinghe PE, Riu F, Dixit P, Edamatsu M, Saxena P, Hamer NS, Galvin IF, Bunton RW, Lequeux S, Jones G, Lamberts RR, Emanueli C, Madeddu P, Katare R (2016) Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway. Int J Cardiol 202:13–20PubMedCrossRef
68.
go back to reference Atkins RC, Zimmet PZ, International Society of, N., International Federation of Kidney Foundations World Kidney Day Steering, C., International Diabetes, F. (2010) Diabetic kidney disease: act now or pay later. Med J Aust 192:272–274PubMedCrossRef Atkins RC, Zimmet PZ, International Society of, N., International Federation of Kidney Foundations World Kidney Day Steering, C., International Diabetes, F. (2010) Diabetic kidney disease: act now or pay later. Med J Aust 192:272–274PubMedCrossRef
69.
go back to reference Rico-Fontalvo J, Aroca G, Cabrales J, Daza-Arnedo R, Yanez-Rodriguez T, Martinez-Avila MC, Uparella-Gulfo I, Raad-Sarabia M (2022) Molecular mechanisms of diabetic kidney disease. Int J Mol Sci. 23 Rico-Fontalvo J, Aroca G, Cabrales J, Daza-Arnedo R, Yanez-Rodriguez T, Martinez-Avila MC, Uparella-Gulfo I, Raad-Sarabia M (2022) Molecular mechanisms of diabetic kidney disease. Int J Mol Sci. 23
70.
go back to reference Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mor A, Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG, Kretzler M, Wanke R, Pavenstadt H, Kerjaschki D, Cohen CD, Hall MN, Ruegg MA, Inoki K, Walz G, Huber TB (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Investig 121:2197–2209PubMedPubMedCentralCrossRef Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mor A, Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG, Kretzler M, Wanke R, Pavenstadt H, Kerjaschki D, Cohen CD, Hall MN, Ruegg MA, Inoki K, Walz G, Huber TB (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Investig 121:2197–2209PubMedPubMedCentralCrossRef
71.
go back to reference Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Asanuma K, Kim EH, Haneda M, Kajiwara N, Hayashi K, Ohashi H, Ugi S, Maegawa H, Uzu T (2016) Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65:755–767PubMedCrossRef Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Asanuma K, Kim EH, Haneda M, Kajiwara N, Hayashi K, Ohashi H, Ugi S, Maegawa H, Uzu T (2016) Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65:755–767PubMedCrossRef
72.
go back to reference Naguib M, Rashed LA (2018) Serum level of the autophagy biomarker Beclin-1 in patients with diabetic kidney disease. Diabetes Res Clin Pract 143:56–61PubMedCrossRef Naguib M, Rashed LA (2018) Serum level of the autophagy biomarker Beclin-1 in patients with diabetic kidney disease. Diabetes Res Clin Pract 143:56–61PubMedCrossRef
73.
go back to reference Yassin R, Tadmor H, Farber E, Igbariye A, Armaly-Nakhoul A, Dahan I, Nakhoul F, Nakhoul N (2021) Alteration of autophagy-related protein 5 (ATG5) levels and Atg5 gene expression in diabetes mellitus with and without complications. Diab Vasc Dis Res 18:14791641211062050PubMedPubMedCentral Yassin R, Tadmor H, Farber E, Igbariye A, Armaly-Nakhoul A, Dahan I, Nakhoul F, Nakhoul N (2021) Alteration of autophagy-related protein 5 (ATG5) levels and Atg5 gene expression in diabetes mellitus with and without complications. Diab Vasc Dis Res 18:14791641211062050PubMedPubMedCentral
74.
go back to reference Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S (2014) Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 44:1026–1036PubMedCrossRef Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S (2014) Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 44:1026–1036PubMedCrossRef
75.
go back to reference Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion AC, Merian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou PE (2020) A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol 72:528–538PubMedCrossRef Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion AC, Merian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou PE (2020) A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol 72:528–538PubMedCrossRef
76.
go back to reference Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, Vargas-Castrillon J, Lo Iacono O, Corazzari M, Fimia GM, Piacentini M, Muntane J, Bosca L, Garcia-Monzon C, Martin-Sanz P, Valverde AM (2014) Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis 5:e1179PubMedPubMedCentralCrossRef Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos MP, Pardo V, Miquilena-Colina ME, Vargas-Castrillon J, Lo Iacono O, Corazzari M, Fimia GM, Piacentini M, Muntane J, Bosca L, Garcia-Monzon C, Martin-Sanz P, Valverde AM (2014) Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis 5:e1179PubMedPubMedCentralCrossRef
77.
go back to reference Fukushima H, Yamashina S, Arakawa A, Taniguchi G, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S (2018) Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease. Hepatol Res 48:757–767PubMedCrossRef Fukushima H, Yamashina S, Arakawa A, Taniguchi G, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S (2018) Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease. Hepatol Res 48:757–767PubMedCrossRef
78.
go back to reference Wang X, Zhang X, Chu ESH, Chen X, Kang W, Wu F, To KF, Wong VWS, Chan HLY, Chan MTV, Sung JJY, Wu WKK, Yu J (2018) Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J 32:37–51PubMedCrossRef Wang X, Zhang X, Chu ESH, Chen X, Kang W, Wu F, To KF, Wong VWS, Chan HLY, Chan MTV, Sung JJY, Wu WKK, Yu J (2018) Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J 32:37–51PubMedCrossRef
79.
go back to reference Ezquerro S, Mocha F, Fruhbeck G, Guzman-Ruiz R, Valenti V, Mugueta C, Becerril S, Catalan V, Gomez-Ambrosi J, Silva C, Salvador J, Colina I, Malagon MM, Rodriguez A (2019) Ghrelin reduces TNF-alpha-induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity-associated NAFLD. J Clin Endocrinol Metab 104:21–37PubMed Ezquerro S, Mocha F, Fruhbeck G, Guzman-Ruiz R, Valenti V, Mugueta C, Becerril S, Catalan V, Gomez-Ambrosi J, Silva C, Salvador J, Colina I, Malagon MM, Rodriguez A (2019) Ghrelin reduces TNF-alpha-induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity-associated NAFLD. J Clin Endocrinol Metab 104:21–37PubMed
80.
go back to reference Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY (2017) Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Oncotarget 8:63370–63381PubMedPubMedCentralCrossRef Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY (2017) Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Oncotarget 8:63370–63381PubMedPubMedCentralCrossRef
81.
go back to reference Moore MP, Cunningham RP, Meers GM, Johnson SA, Wheeler AA, Ganga RR, Spencer NM, Pitt JB, Diaz-Arias A, Swi AIA, Hammoud GM, Ibdah JA, Parks EJ, Rector RS (2022) Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD. Hepatology 76:1452–1465PubMedCrossRef Moore MP, Cunningham RP, Meers GM, Johnson SA, Wheeler AA, Ganga RR, Spencer NM, Pitt JB, Diaz-Arias A, Swi AIA, Hammoud GM, Ibdah JA, Parks EJ, Rector RS (2022) Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD. Hepatology 76:1452–1465PubMedCrossRef
82.
go back to reference Barrientos-Riosalido A, Real M, Bertran L, Aguilar C, Martinez S, Parada D, Vives M, Sabench F, Riesco D, Castillo DD, Richart C, Auguet T (2023) Increased hepatic ATG7 mRNA and ATG7 protein expression in nonalcoholic steatohepatitis associated with obesity. Int J Mol Sci 24:1324PubMedPubMedCentralCrossRef Barrientos-Riosalido A, Real M, Bertran L, Aguilar C, Martinez S, Parada D, Vives M, Sabench F, Riesco D, Castillo DD, Richart C, Auguet T (2023) Increased hepatic ATG7 mRNA and ATG7 protein expression in nonalcoholic steatohepatitis associated with obesity. Int J Mol Sci 24:1324PubMedPubMedCentralCrossRef
83.
go back to reference Baselli GA, Jamialahmadi O, Pelusi S, Ciociola E, Malvestiti F, Saracino M, Santoro L, Cherubini A, Dongiovanni P, Maggioni M, Bianco C, Tavaglione F, Cespiati A, Mancina RM, D’Ambrosio R, Vaira V, Petta S, Miele L, Vespasiani-Gentilucci U, Federico A, Pihlajamaki J, Bugianesi E, Fracanzani AL, Reeves HL, Soardo G, Prati D, Romeo S, Valenti LV, Investigators ES (2022) Rare ATG7 genetic variants predispose patients to severe fatty liver disease. J Hepatol 77:596–606PubMedCrossRef Baselli GA, Jamialahmadi O, Pelusi S, Ciociola E, Malvestiti F, Saracino M, Santoro L, Cherubini A, Dongiovanni P, Maggioni M, Bianco C, Tavaglione F, Cespiati A, Mancina RM, D’Ambrosio R, Vaira V, Petta S, Miele L, Vespasiani-Gentilucci U, Federico A, Pihlajamaki J, Bugianesi E, Fracanzani AL, Reeves HL, Soardo G, Prati D, Romeo S, Valenti LV, Investigators ES (2022) Rare ATG7 genetic variants predispose patients to severe fatty liver disease. J Hepatol 77:596–606PubMedCrossRef
84.
go back to reference Lake AD, Novak P, Hardwick RN, Flores-Keown B, Zhao F, Klimecki WT, Cherrington NJ (2014) The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 137:26–35PubMedCrossRef Lake AD, Novak P, Hardwick RN, Flores-Keown B, Zhao F, Klimecki WT, Cherrington NJ (2014) The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 137:26–35PubMedCrossRef
86.
go back to reference Zeng J, Acin-Perez R, Assali EA, Martin A, Brownstein AJ, Petcherski A, Fernandez-Del-Rio L, Xiao R, Lo CH, Shum M, Liesa M, Han X, Shirihai OS, Grinstaff MW (2023) Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease. Nat Commun 14:2573PubMedPubMedCentralCrossRef Zeng J, Acin-Perez R, Assali EA, Martin A, Brownstein AJ, Petcherski A, Fernandez-Del-Rio L, Xiao R, Lo CH, Shum M, Liesa M, Han X, Shirihai OS, Grinstaff MW (2023) Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease. Nat Commun 14:2573PubMedPubMedCentralCrossRef
87.
go back to reference Bagherniya M, Butler AE, Barreto GE, Sahebkar A (2018) The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res Rev 47:183–197PubMedCrossRef Bagherniya M, Butler AE, Barreto GE, Sahebkar A (2018) The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res Rev 47:183–197PubMedCrossRef
88.
go back to reference Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H (2018) Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep 6:e13651PubMedPubMedCentralCrossRef Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H (2018) Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep 6:e13651PubMedPubMedCentralCrossRef
89.
go back to reference Ezpeleta M, Gabel K, Cienfuegos S, Kalam F, Lin S, Pavlou V, Song Z, Haus JM, Koppe S, Alexandria SJ, Tussing-Humphreys L, Varady KA (2023) Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab 35(56–70):e3 Ezpeleta M, Gabel K, Cienfuegos S, Kalam F, Lin S, Pavlou V, Song Z, Haus JM, Koppe S, Alexandria SJ, Tussing-Humphreys L, Varady KA (2023) Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab 35(56–70):e3
90.
go back to reference Marino G, Pietrocola F, Madeo F, Kroemer G (2014) Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Autophagy 10:1879–1882PubMedPubMedCentralCrossRef Marino G, Pietrocola F, Madeo F, Kroemer G (2014) Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Autophagy 10:1879–1882PubMedPubMedCentralCrossRef
91.
go back to reference Kepp O, Chen G, Carmona-Gutierrez D, Madeo F, Kroemer G (2020) A discovery platform for the identification of caloric restriction mimetics with broad health-improving effects. Autophagy 16:188–189PubMedCrossRef Kepp O, Chen G, Carmona-Gutierrez D, Madeo F, Kroemer G (2020) A discovery platform for the identification of caloric restriction mimetics with broad health-improving effects. Autophagy 16:188–189PubMedCrossRef
92.
go back to reference Xiang M, Yuan X, Zhang N, Zhang L, Liu Y, Liu J, Gao Y, Xu Y, Sun W, Tang Q, Zhang Y, Lu J (2024) Effects of exercise, metformin, and combination treatments on type 2 diabetic mellitus-induced muscle atrophy in db/db mice: crosstalk between autophagy and the proteasome. J Physiol Biochem 80:235–247PubMedCrossRef Xiang M, Yuan X, Zhang N, Zhang L, Liu Y, Liu J, Gao Y, Xu Y, Sun W, Tang Q, Zhang Y, Lu J (2024) Effects of exercise, metformin, and combination treatments on type 2 diabetic mellitus-induced muscle atrophy in db/db mice: crosstalk between autophagy and the proteasome. J Physiol Biochem 80:235–247PubMedCrossRef
94.
go back to reference Abad-Jimenez Z, Lopez-Domenech S, Diaz-Rua R, Iannantuoni F, Gomez-Abril SA, Perianez-Gomez D, Morillas C, Victor VM, Rocha M (2020) Systemic oxidative stress and visceral adipose tissue mediators of NLRP3 inflammasome and autophagy are reduced in obese type 2 diabetic patients treated with metformin. Antioxidants 9:892PubMedPubMedCentralCrossRef Abad-Jimenez Z, Lopez-Domenech S, Diaz-Rua R, Iannantuoni F, Gomez-Abril SA, Perianez-Gomez D, Morillas C, Victor VM, Rocha M (2020) Systemic oxidative stress and visceral adipose tissue mediators of NLRP3 inflammasome and autophagy are reduced in obese type 2 diabetic patients treated with metformin. Antioxidants 9:892PubMedPubMedCentralCrossRef
95.
go back to reference Lopaschuk GD, Verma S (2020) Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 5:632–644PubMedPubMedCentralCrossRef Lopaschuk GD, Verma S (2020) Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 5:632–644PubMedPubMedCentralCrossRef
96.
go back to reference Furuya F, Fujita Y, Matsuo N, Minamino H, Oguri Y, Isomura N, Ikeda K, Takesue K, Li Y, Kondo A, Mano F, Inagaki N (2022) Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin. EBioMedicine 86:104342PubMedPubMedCentralCrossRef Furuya F, Fujita Y, Matsuo N, Minamino H, Oguri Y, Isomura N, Ikeda K, Takesue K, Li Y, Kondo A, Mano F, Inagaki N (2022) Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin. EBioMedicine 86:104342PubMedPubMedCentralCrossRef
97.
go back to reference Li T, Fang T, Xu L, Liu X, Li X, Xue M, Yu X, Sun B, Chen L (2020) Empagliflozin alleviates hepatic steatosis by activating the AMPK-TET2-autophagy pathway in vivo and in vitro. Front Pharmacol 11:622153PubMedCrossRef Li T, Fang T, Xu L, Liu X, Li X, Xue M, Yu X, Sun B, Chen L (2020) Empagliflozin alleviates hepatic steatosis by activating the AMPK-TET2-autophagy pathway in vivo and in vitro. Front Pharmacol 11:622153PubMedCrossRef
98.
go back to reference Yaribeygi H, Maleki M, Santos RD, Jamialahmadi T, Sahebkar A (2024) Glp-1 mimetics and autophagy in diabetic milieu: state-of-the-art. Curr Diabetes Rev 20:93–101CrossRef Yaribeygi H, Maleki M, Santos RD, Jamialahmadi T, Sahebkar A (2024) Glp-1 mimetics and autophagy in diabetic milieu: state-of-the-art. Curr Diabetes Rev 20:93–101CrossRef
99.
go back to reference He Q, Sha S, Sun L, Zhang J, Dong M (2016) GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem Biophys Res Commun 476:196–203PubMedCrossRef He Q, Sha S, Sun L, Zhang J, Dong M (2016) GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem Biophys Res Commun 476:196–203PubMedCrossRef
100.
go back to reference He Y, Ao N, Yang J, Wang X, Jin S, Du J (2020) The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy. Ann Hepatol 19:44–52PubMedCrossRef He Y, Ao N, Yang J, Wang X, Jin S, Du J (2020) The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy. Ann Hepatol 19:44–52PubMedCrossRef
101.
go back to reference Fang Y, Ji L, Zhu C, Xiao Y, Zhang J, Lu J, Yin J, Wei L (2020) Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway. Front Cell Dev Biol 8:602574PubMedPubMedCentralCrossRef Fang Y, Ji L, Zhu C, Xiao Y, Zhang J, Lu J, Yin J, Wei L (2020) Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway. Front Cell Dev Biol 8:602574PubMedPubMedCentralCrossRef
102.
go back to reference Yu S, Wang Z, Ding L, Yang L (2020) The regulation of TFEB in lipid homeostasis of non-alcoholic fatty liver disease: molecular mechanism and promising therapeutic targets. Life Sci 246:117418PubMedCrossRef Yu S, Wang Z, Ding L, Yang L (2020) The regulation of TFEB in lipid homeostasis of non-alcoholic fatty liver disease: molecular mechanism and promising therapeutic targets. Life Sci 246:117418PubMedCrossRef
103.
go back to reference Shao N, Yu XY, Ma XF, Lin WJ, Hao M, Kuang HY (2018) Exenatide delays the progression of nonalcoholic fatty liver disease in C57BL/6 Mice, which may involve inhibition of the NLRP3 inflammasome through the mitophagy pathway. Gastroenterol Res Pract 2018:1864307PubMedPubMedCentralCrossRef Shao N, Yu XY, Ma XF, Lin WJ, Hao M, Kuang HY (2018) Exenatide delays the progression of nonalcoholic fatty liver disease in C57BL/6 Mice, which may involve inhibition of the NLRP3 inflammasome through the mitophagy pathway. Gastroenterol Res Pract 2018:1864307PubMedPubMedCentralCrossRef
104.
go back to reference Ding S, Jiang J, Zhang G, Bu Y, Zhang G, Zhao X (2017) Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats. PLoS ONE 12:e0183541PubMedPubMedCentralCrossRef Ding S, Jiang J, Zhang G, Bu Y, Zhang G, Zhao X (2017) Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats. PLoS ONE 12:e0183541PubMedPubMedCentralCrossRef
105.
go back to reference Li L, Hai J, Li Z, Zhang Y, Peng H, Li K, Weng X (2014) Resveratrol modulates autophagy and NF-kappaB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol 63:166–173PubMedCrossRef Li L, Hai J, Li Z, Zhang Y, Peng H, Li K, Weng X (2014) Resveratrol modulates autophagy and NF-kappaB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol 63:166–173PubMedCrossRef
106.
go back to reference Madeo F, Eisenberg T, Pietrocola F, Kroemer G (2018) Spermidine in health and disease. Science 359:eaan2788PubMedCrossRef Madeo F, Eisenberg T, Pietrocola F, Kroemer G (2018) Spermidine in health and disease. Science 359:eaan2788PubMedCrossRef
107.
go back to reference Barber TM, Kabisch S, Randeva HS, Pfeiffer AFH, Weickert MO (2022) Implications of resveratrol in obesity and insulin resistance: a state-of-the-art review. Nutrients 14:2870PubMedPubMedCentralCrossRef Barber TM, Kabisch S, Randeva HS, Pfeiffer AFH, Weickert MO (2022) Implications of resveratrol in obesity and insulin resistance: a state-of-the-art review. Nutrients 14:2870PubMedPubMedCentralCrossRef
108.
go back to reference Gu W, Geng J, Zhao H, Li X, Song G (2022) Effects of resveratrol on metabolic indicators in patients with type 2 diabetes: a systematic review and meta-analysis. Int J Clin Pract 2022:9734738PubMedPubMedCentralCrossRef Gu W, Geng J, Zhao H, Li X, Song G (2022) Effects of resveratrol on metabolic indicators in patients with type 2 diabetes: a systematic review and meta-analysis. Int J Clin Pract 2022:9734738PubMedPubMedCentralCrossRef
109.
go back to reference Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, Muller M, Schrauwen P, Mariman EC, Blaak EE (2014) The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes 38:470–473CrossRef Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, Muller M, Schrauwen P, Mariman EC, Blaak EE (2014) The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes 38:470–473CrossRef
110.
go back to reference Zou D, Zhao Z, Li L, Min Y, Zhang D, Ji A, Jiang C, Wei X, Wu X (2022) A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing. Compr Rev Food Sci Food Saf 21:2820–2842PubMedCrossRef Zou D, Zhao Z, Li L, Min Y, Zhang D, Ji A, Jiang C, Wei X, Wu X (2022) A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing. Compr Rev Food Sci Food Saf 21:2820–2842PubMedCrossRef
111.
go back to reference Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, Fu Z (2020) Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes 12:1–19PubMedCrossRef Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, Fu Z (2020) Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes 12:1–19PubMedCrossRef
112.
go back to reference Choksomngam Y, Pattanakuhar S, Chattipakorn N, Chattipakorn SC (2021) The metabolic role of spermidine in obesity: evidence from cells to community. Obes Res Clin Pract 15:315–326PubMedCrossRef Choksomngam Y, Pattanakuhar S, Chattipakorn N, Chattipakorn SC (2021) The metabolic role of spermidine in obesity: evidence from cells to community. Obes Res Clin Pract 15:315–326PubMedCrossRef
Metadata
Title
Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies
Authors
Patrycja Jakubek
Barbara Pakula
Martin Rossmeisl
Paolo Pinton
Alessandro Rimessi
Mariusz Roman Wieckowski
Publication date
06-07-2024
Publisher
Springer International Publishing
Published in
Internal and Emergency Medicine
Print ISSN: 1828-0447
Electronic ISSN: 1970-9366
DOI
https://doi.org/10.1007/s11739-024-03700-w
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