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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic diseases including fatty liver, or bland steatosis, as well as more aggressive lesions including steatohepatitis, lobular necroinflammation with fibrosis, or cirrhosis
Microscopic observations of free fatty acids (FFA) treated primary human hepatocytes revealed that conspicuous steatosis (Fig. 1A) were caused by the cis, trans-unsaturated, and saturated fatty acids
We treated human hepatocytes engorged with Free fatty acids (FFA) with exendin-4 to first determine if it led to reduction in FFA stores; and, whether exendin-4 protected such hepatocytes from apoptosis
Summary
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic diseases including fatty liver, or bland steatosis, as well as more aggressive lesions including steatohepatitis, lobular necroinflammation with fibrosis, or cirrhosis. NAFLD-related cirrhosis can lead to end-stage liver disease and hepatocellular carcinoma (HCC). Like other chronic end-stage liver diseases the major option for afflicted persons is liver transplantation. Recent evidence indicates that such fatty acids are partly, responsible for inducing steatosis and fueling hepatocyte insulin resistance [2]. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. 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
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