Published in:
01-06-2016 | Commentary
The liver in focus
Published in: Diabetologia | Issue 6/2016
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The liver is not only responsible for handling carbohydrates and lipids, but is also a key signalling organ, producing hormones (hepatokines) and receiving signals from other tissues. Nevertheless, studies on the liver in diabetes mellitus have focused on its role in alterating glucose fluxes (Fig. 1). Although the association of non-alcoholic fatty liver disease (NAFLD) with obesity and type 2 diabetes is very well established, it is only recently that studies have addressed other aspects of hepatic metabolism, particularly lipid fluxes and energy balance. Likewise, the clinical relevance of NAFLD has long been the subject of study. Given its role as a risk factor for hepatocellular carcinoma and cardiovascular diseases, a critical analysis of NAFLD pathophysiology, diagnostic procedures and therapeutic measures is vital to fight this common comorbidity of obesity and type 2 diabetes. The following series of mini-reviews summarises the contributions of leading researchers in this field presented at a symposium at the 51st EASD annual meeting in Stockholm in September 2015.
Fig. 1
Cellular mechanisms linking diabetes and metabolic liver diseases. High-energy diets increase the flux of NEFA and glucose to hepatocytes. Likewise, in obesity and insulin resistant states, the flux of NEFA, glucose and lactate is re-directed to the liver, and cytokines mainly originating from inflamed adipose tissue, infiltrated by macrophages (MΦ), enter the liver. Within the hepatocytes, fatty acyl-coenzyme A (FA-CoA), via diacylglycerol (DAG) or ceramides, inhibits insulin signalling at the level of the insulin receptor (IR) or Akt2 and thereby causes insulin resistance. Furthermore, the FA-CoA pool, as a precursor of triacylglycerol (TAG), is further enlarged by de novo lipogenesis (DNL), controlled by sterol- and carbohydrate-responsive enhancing binding proteins (SREBP and ChREBP), and decreased by β oxidation (βOX). TAG can be released in the form of VLDL or stored in lipid droplets, where it undergoes turnover catalysed by hydrolases and acyltransferases such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is involved in the development of NAFLD independently of insulin resistance. Enhanced mitochondrial activity can give rise to reactive oxygen species (ROS) and thereby generate oxidative stress with apoptosis and activate inflammatory pathways (c-Jun N-terminal kinase [JNK]/inhibitor of κB kinase [IKK]). Finally, accumulation of acetyl-CoA serves as a precursor for gluconeogenesis (GNG) and thereby raises endogenous glucose production and causes hyperglycaemia. AC, adipocyte; CETP, cholesterylester transfer protein; MC, muscle cell; TLR4, Toll-like receptor 4
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