Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway

Abstract

Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-γ (PPARγ), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPARγ signaling pathway.NAFLD | gastric hormone | growth hormone secretagogue receptor | GHSR T riglyceride deposition in the liver, which is strongly associated with obesity, is the initial event in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Over time, hepatic steatosis may progress to steatohepatitis, cirrhosis, and primary hepatocellular carcinoma (1). The current therapeutic strategy for NAFLD has been focused on reversal of hepatic steatosis, primarily through weight reduction. Treatment is often ineffective because of the difficulty in achieving sustained weight loss. Alternative approaches are needed but are limited by incomplete understanding of the mechanisms controlling the development of steatosis. Gastric hormones may be involved in regulation of lipid metabolism. Studies in both animals and humans demonstrate that ghrelin, a 28-aa peptide hormone secreted by X/A-like endocrine cells in the gastric fundus (2, 3), stimulates lipid accumulation in adipose tissue (4). Chronic infusion of ghrelin increases both adipose and hepatic lipid storage (5). Genetic disruption of either ghrelin or ghrelin receptor genes renders mice resistant to obesity and to the development of hepatic steatosis (6). Interestingly, the anabolic effect of ghrelin appears to be independent of its hyperphagic action. Chronic third intracerebroventricular infusion of ghrelin in diet-induced obese rats increases adiposity and gene expression of lipogenic enzymes in white adipose tissue while food intake remains unchanged (7)....

Ghrelin Stimulates Hepatocyte Proliferation via Regulating Cell Cycle Through GSK3β/Β-Catenin Signaling Pathway

“…GHSR1a expression levels increase significantly in hepatocytes isolated from steatotic liver as well as upon exposure to ghrelin, indicating the plasticity nature of GHS-R1a. Consistent with this observation, our previous study demonstrates the cytoplasm membrane binding of rhodamine-labeled ghrelin in hepatocytes stained positively for albumin [28]. Further, incubation of hepatocytes with rhodamine-ghrelin demonstrates rapid receptor internalization typical of G protein coupled receptor [28].…”

Effects of ghrelin in energy balance and body weight homeostasis

“…91 Studies on laboratory animals have revealed that under the action of acyl-ghrelin, fat is stored not only in adipose tissue but also the liver, 39 where an increase in triacylglycerol content and genes involved in hepatic lipogenesis was found. 92 A recent study published by Gagnon et al brought up for discussion a new aspect of ghrelin involvement in glucose regulation, the authors demonstrating that ghrelin increases the secretion of GLP-1 (glucagon like peptide 1), thereby improving glucose tolerance. 93 They concluded that ghrelin is a "GLP-1 secretagogue".…”

“…In conclusion, circulating ghrelin level in humans are low under conditions of positive energy balance, Table 1. The main effects of ghrelin that can influence energy metabolism Food intake 1,35 ↑ appetite/↑ food intake ↑ hedonic aspect of eating ↑ motivation to obtain food ↑ food seeking behaviours Gastrointestinal function [47][48][49][50] ↑ gastric motility ↑ gastric acid secretion and digestive enzymes Adipose tissue 26,39,53,58 ↑ lipogenesis ↑ adipogenesis (↑ differentiation and proliferation of preadipocytes) ↓ lipid oxidation Intermediary metabolisms 57,62,79,82,90,92,93 ↓ insulin secretion ↑ hepatic gluconeogenesis ↓ insulin sensitivity ↑ glucagon secretion ↑ hepatic lipogenesis GLP-1 secretagogue Energy expenditure 52,57,94,95 ↓ energy expenditure ↓ thermogenesis in BAT ↓ sympathetic nervous system in BAT either in acute conditions (food intake) or chronic conditions (obesity). Elevated circulating ghrelin levels are found in fasting conditions and in patients with anorexia of various causes.…”

High-Concentrate Diet-Induced Change of Cellular Metabolism Leads to Decreases of Immunity and Imbalance of Cellular Activities in Rumen Epithelium

“…Previous studies have demonstrated that the upregulation of the mTOR signaling pathway is one of the most commonly observed pathological alterations in the cancer cells [31]. Moreover, the upregulation of the mTOR-PPAR signaling pathway promotes lipid accumulation in the liver and therefore contributes to the obesity-induced dysfunction of the immune system and metabolism [32]. Then, the upregulation of the MAPK signaling pathway exaggerates the growth effects of insulin on the cells and promotes the autophagy and apoptosis processes of the cells [33].…”