GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy

Abstract

BackgroundNonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress- induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Methodology/Principal FindingsPrimary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide. Conclusions/SignificanceGLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

XBP1s Is an Anti-lipogenic Protein

“…In response to starvation, LC3BII association with lipid droplets and subsequent initiation of macrolipophagy is increased in healthy, lean mice, and this process is blunted in DIO mice (34). Excess nutrient supply, such as prolonged HFD feeding, has been reported to reduce autophagy efficiency, thereby contributing to the development of ER stress and insulin resistance (45)(46)(47). The vicious cycle in which increased cellular lipid content impairs macrolipophagy, which then further reduces autophagic function, eventually leads to more lipid retention.…”

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

“…51) Liraglutide has also been reported to reduce hepatic steatosis and endoplasmic reticulum (ER) stress in mice fed with a high fat diet. 52) Another GLP-1 analogue, exendin-4, has been demonstrated to decrease the fatty acid load in hepatocytes and reverse hepatic steatosis in obese mice. 53,54) In the present study, our results confirmed that liraglutide decreased body weight, increased insulin sensitivity, reduced hepatic lipid accumulation and consequently decreased serum ALT levels, which indicated that liraglutide might have a liver protective effect in the rats with HFHC diet-induced NAFLD.…”

Regulation of lipid stores and metabolism by lipophagy

“…80 Future investigations will likely determine that autophagy in metabolically active cells, such as hepatocytes and pancreatic b cells, is regulated by multiple serum factors that are altered with obesity and insulin resistance such as glucagon-like peptide 1. 89 …”