Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2014

Open Access 01-12-2014 | Review

A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy

Authors: Ren Zhang, Abdul B Abou-Samra

Published in: Cardiovascular Diabetology | Issue 1/2014

Login to get access

Abstract

Metabolic syndrome includes glucose intolerance and dyslipidemia, both of which are strong risk factors for developing diabetes and atherosclerotic cardiovascular diseases. Recently, multiple groups independently studied a previously uncharacterized gene, officially named C19orf80 (human) and Gm6484 (mouse), but more commonly known as RIFL, Angptl8, betatrophin and lipasin. Both exciting and conflicting results have been obtained, and significant controversy is ongoing. Accumulating evidence from genome wide association studies and mouse genetic studies convincingly shows that lipasin is involved in lipid regulation. However, the mechanism of action, the identity of transcription factors mediating its nutritional regulation, circulating levels, and relationship among lipasin, Angptl3 and Angptl4, remain elusive. Betatrophin represents a promising drug target for replenishing β-cell mass, but current results have not been conclusive regarding its potency and specificity. Here, we summarize the consensus and controversy regarding functions of lipasin/betatrophin based on currently available evidence.
Appendix
Available only for authorised users
Literature
1.
Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet. 2005, 365: 1415-1428. 10.1016/S0140-6736(05)66378-7.CrossRefPubMed
2.
Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC, Sowers JR: Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999, 100: 1134-1146. 10.1161/01.CIR.100.10.1134.CrossRefPubMed
3.
Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH: Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation. 2004, 110: 2952-2967. 10.1161/01.CIR.0000145546.97738.1E.CrossRefPubMed
4.
Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S: Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011, 123: 2292-2333. 10.1161/CIR.0b013e3182160726.CrossRefPubMed
5.
Haffner SM: Management of dyslipidemia in adults with diabetes. Diabetes Care. 2003, 26 (Suppl 1): S83-S86.PubMed
6.
Mooradian AD: Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009, 5: 150-159. 10.1038/ncpendmet1066.CrossRefPubMed
7.
Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, Gotto AM, Patsch W: Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb. 1992, 12: 1336-1345. 10.1161/01.ATV.12.11.1336.CrossRefPubMed
8.
Kersten S: Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 1841, 2014: 919-933.
9.
Santamarina-Fojo S, Brewer HB: The familial hyperchylomicronemia syndrome. New insights into underlying genetic defects. JAMA. 1991, 265: 904-908. 10.1001/jama.1991.03460070086049.CrossRefPubMed
10.
Coleman T, Seip RL, Gimble JM, Lee D, Maeda N, Semenkovich CF: COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity. J Biol Chem. 1995, 270: 12518-12525. 10.1074/jbc.270.21.12518.CrossRefPubMed
11.
Weinstock PH, Bisgaier CL, Aalto-Setala K, Radner H, Ramakrishnan R, Levak-Frank S, Essenburg AD, Zechner R, Breslow JL: Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest. 1995, 96: 2555-2568. 10.1172/JCI118319.PubMedCentralCrossRefPubMed
12.
Beigneux AP, Davies BS, Gin P, Weinstein MM, Farber E, Qiao X, Peale F, Bunting S, Walzem RL, Wong JS, Blaner WS, Ding ZM, Melford K, Wongsiriroj N, Shu X, de Sauvage F, Ryan RO, Fong LG, Bensadoun A, Young SG: Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 2007, 5: 279-291. 10.1016/j.cmet.2007.02.002.PubMedCentralCrossRefPubMed
13.
Beigneux AP, Franssen R, Bensadoun A, Gin P, Melford K, Peter J, Walzem RL, Weinstein MM, Davies BS, Kuivenhoven JA, Kastelein JJ, Fong LG, Dallinga-Thie GM, Young SG: Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler Thromb Vasc Biol. 2009, 29: 956-962. 10.1161/ATVBAHA.109.186577.PubMedCentralCrossRefPubMed
14.
Gray KA, Daugherty LC, Gordon SM, Seal RL, Wright MW, Bruford EA: Genenames.org: the HGNC resources in 2013. Nucleic Acids Res. 2013, 41: D545-D552. 10.1093/nar/gks1066.PubMedCentralCrossRefPubMed
15.
Ren G, Kim JY, Smas CM: Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012, 303: E334-E351. 10.1152/ajpendo.00084.2012.PubMedCentralCrossRefPubMed
16.
Fu Z, Yao F, Abou-Samra AB, Zhang R: Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun. 2013, 430: 1126-1131. 10.1016/j.bbrc.2012.12.025.CrossRefPubMed
17.
Zhang R: Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012, 424: 786-792. 10.1016/j.bbrc.2012.07.038.CrossRefPubMed
18.
Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, Zhang R: Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci Rep. 2014, 4: 5013-PubMed
19.
Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH: Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci U S A. 2012, 109: 19751-19756. 10.1073/pnas.1217552109.PubMedCentralCrossRefPubMed
20.
Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH: Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci U S A. 2013, 110: 16109-16114. 10.1073/pnas.1315292110.PubMedCentralCrossRefPubMed
21.
Yi P, Park JS, Melton DA: Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell. 2013, 153: 747-758. 10.1016/j.cell.2013.04.008.PubMedCentralCrossRefPubMed
22.
Espes D, Lau J, Carlsson PO: Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014, 57: 50-53. 10.1007/s00125-013-3071-1.PubMedCentralCrossRefPubMed
23.
Espes D, Martinell M, Carlsson PO: Increased circulating betatrophin concentrations in patients with type 2 diabetes. Int J Endocrinol. 2014, 2014: 323407-10.1155/2014/323407.PubMedCentralCrossRefPubMed
24.
Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M, Kautzky-Willer A, Stulnig TM, Kiefer FW: Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014, 57: 1204-1208. 10.1007/s00125-014-3208-x.CrossRefPubMed
25.
Tseng YH, Ke PY, Liao CJ, Wu SM, Chi HC, Tsai CY, Chen CY, Lin YH, Lin KH: Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism. Autophagy. 2014, 10: 20-31. 10.4161/auto.26126.CrossRefPubMed
26.
Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA: An integrated map of genetic variation from 1,092 human genomes. Nature. 2012, 491: 56-65. 10.1038/nature11632.CrossRefPubMed
27.
Peloso GM, Auer PL, Bis JC, Voorman A, Morrison AC, Stitziel NO, Brody JA, Khetarpal SA, Crosby JR, Fornage M, Isaacs A, Jakobsdottir J, Feitosa MF, Davies G, Huffman JE, Manichaikul A, Davis B, Lohman K, Joon AY, Smith AV, Grove ML, Zanoni P, Redon V, Demissie S, Lawson K, Peters U, Carlson C, Jackson RD, Ryckman KK, Mackey RH, et al: Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014, 94: 223-232. 10.1016/j.ajhg.2014.01.009.PubMedCentralCrossRefPubMed
28.
Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, et al: Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010, 466: 707-713. 10.1038/nature09270.PubMedCentralCrossRefPubMed
29.
Weissglas-Volkov D, Aguilar-Salinas CA, Nikkola E, Deere KA, Cruz-Bautista I, Arellano-Campos O, Munoz-Hernandez LL, Gomez-Munguia L, Ordonez-Sanchez ML, Reddy PM, Lusis AJ, Matikainen N, Taskinen MR, Riba L, Cantor RM, Sinsheimer JS, Tusie-Luna T, Pajukanta P: Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci. J Med Genet. 2013, 50: 298-308. 10.1136/jmedgenet-2012-101461.PubMedCentralCrossRefPubMed
30.
Tang T, Li L, Tang J, Li Y, Lin WY, Martin F, Grant D, Solloway M, Parker L, Ye W, Forrest W, Ghilardi N, Oravecz T, Platt KA, Rice DS, Hansen GM, Abuin A, Eberhart DE, Godowski P, Holt KH, Peterson A, Zambrowicz BP, de Sauvage FJ: A mouse knockout library for secreted and transmembrane proteins. Nat Biotechnol. 2010, 28: 749-755. 10.1038/nbt.1644.CrossRefPubMed
31.
Mattijssen F, Kersten S: Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 1821, 2012: 782-789.
32.
Ono M, Shimizugawa T, Shimamura M, Yoshida K, Noji-Sakikawa C, Ando Y, Koishi R, Furukawa H: Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. J Biol Chem. 2003, 278: 41804-41809. 10.1074/jbc.M302861200.CrossRefPubMed
33.
Camenisch G, Pisabarro MT, Sherman D, Kowalski J, Nagel M, Hass P, Xie MH, Gurney A, Bodary S, Liang XH, Clark K, Beresini M, Ferrara N, Gerber HP: ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo. J Biol Chem. 2002, 277: 17281-17290. 10.1074/jbc.M109768200.CrossRefPubMed
34.
Eckel RH: Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Med. 1989, 320: 1060-1068. 10.1056/NEJM198904203201607.CrossRefPubMed
35.
Zhang R, Abou-Samra AB: Emerging roles of Lipasin as a critical lipid regulator. Biochem Biophys Res Commun. 2013, 432: 401-405. 10.1016/j.bbrc.2013.01.129.CrossRefPubMed
36.
Leanca CC, Nunes VS, Panzoldo NB, Zago VS, Parra ES, Cazita PM, Jauhiainen M, Passarelli M, Nakandakare ER, de Faria EC, Quintao EC: Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects. Cardiovasc Diabetol. 2013, 12: 173-10.1186/1475-2840-12-173.PubMedCentralCrossRefPubMed
37.
Huang Y, Li X, Wang M, Ning H, Li Y, Sun C: Lipoprotein lipase links vitamin D, insulin resistance, and type 2 diabetes: a cross-sectional epidemiological study. Cardiovasc Diabetol. 2013, 12: 17-10.1186/1475-2840-12-17.PubMedCentralCrossRefPubMed
38.
Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, Wang D, Yang L, Wang J, Mao C, Zhou L, Yuan G: Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients.Diabetes Care 2014. in press.,
39.
Parsons JA, Brelje TC, Sorenson RL: Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology. 1992, 130: 1459-1466.PubMed
40.
Alonso LC, Yokoe T, Zhang P, Scott DK, Kim SK, O'Donnell CP, Garcia-Ocana A: Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes. 2007, 56: 1792-1801. 10.2337/db06-1513.PubMedCentralCrossRefPubMed
41.
Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR: Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997, 88: 561-572. 10.1016/S0092-8674(00)81896-6.CrossRefPubMed
42.
Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR: PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest. 2004, 114: 828-836. 10.1172/JCI21845.PubMedCentralCrossRefPubMed
43.
Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR: Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000, 6: 87-97. 10.1016/S1097-2765(00)00010-1.CrossRefPubMed
44.
El Ouaamari A, Kawamori D, Dirice E, Liew CW, Shadrach JL, Hu J, Katsuta H, Hollister-Lock J, Qian WJ, Wagers AJ, Kulkarni RN: Liver-derived systemic factors drive beta cell hyperplasia in insulin-resistant states. Cell Rep. 2013, 3: 401-410. 10.1016/j.celrep.2013.01.007.PubMedCentralCrossRefPubMed
45.
Jiao Y, Le Lay J, Yu M, Naji A, Kaestner KH: Elevated mouse hepatic betatrophin expression does not increase human beta-cell replication in the transplant setting. Diabetes. 2014, 63: 1283-1288. 10.2337/db13-1435.PubMedCentralCrossRefPubMed
46.
Stewart AF: Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in beta-cell regeneration research. Diabetes. 2014, 63: 1198-1199. 10.2337/db14-0009.PubMedCentralCrossRefPubMed
47.
Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM: A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012, 481: 463-468. 10.1038/nature10777.PubMedCentralCrossRefPubMed
48.
Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T, Yang LJ, Tang D: Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014, 63: 514-525. 10.2337/db13-1106.CrossRefPubMed
49.
Sanchis-Gomar F, Perez-Quilis C: The p38-PGC-1alpha-irisin-betatrophin axis: Exploring new pathways in insulin resistance. Adipocyte. 2014, 3: 67-68. 10.4161/adip.27370.PubMedCentralCrossRefPubMed
50.
Gomez-Ambrosi J, Pascual E, Catalan V, Rodriguez A, Ramirez B, Silva C, Gil MJ, Salvador J, Fruhbeck G: Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes.J Clin Endocrinol Metab 2014. in press.,
51.
Fu Z, Abou-Samra AB, Zhang R: An explanation for recent discrepancies in levels of human circulating betatrophin. Diabetologia. 2014, 57: 2232-2234. 10.1007/s00125-014-3346-1.CrossRefPubMed
52.
Chang JK, Lyu RM, Chen XQ, Tian Q, Sabirov A, Dun SL, Dun NJ: Detection of C-terminal betatrophin peptides in human plasma and rodent liver. Detection of C-terminal betatrophin peptides in human plasma and rodent liver. The 4th Asia-Pacific International Peptide Symposium. Peptide Science, Japan. Edited by: Nishiuchi Y, Teshima T. 2013, 243-246.
Metadata
Title
A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy
Authors
Ren Zhang
Abdul B Abou-Samra
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2014
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-014-0133-8

Other articles of this Issue 1/2014

Cardiovascular Diabetology 1/2014 Go to the issue

Original investigation

Disruption of endothelial adherens junctions by high glucose is mediated by protein kinase C-β–dependent vascular endothelial cadherin tyrosine phosphorylation

Review

Do incretins improve endothelial function?

Original investigation

PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors

Original investigation

Impaired dopamine D1 receptor-mediated vasorelaxation of mesenteric arteries in obese Zucker rats

Original investigation

Body adiposity dictates different mechanisms of increased coronary reactivity related to improved in vivo cardiac function

Original investigation

Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits