Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes
Journal
International Journal of Obesity
Journal Volume
43
Journal Issue
12
Pages
2469-2479
Date Issued
2019
Author(s)
Abstract
Background: Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. Methods: Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. Results: The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. Conclusions: Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC. ? 2019, The Author(s), under exclusive licence to Springer Nature Limited.
SDGs
Other Subjects
acetyl coenzyme A carboxylase; androgen receptor; calphostin C; cerulenin; diacylglycerol; fatty acid synthase; leukemia inhibitory factor receptor; metformin; oleic acid; palmitic acid; palmitoleic acid; phosphatidate phosphatase; protein kinase B; protein kinase C epsilon; short hairpin RNA; stearic acid; triacylglycerol; androgen receptor; diacylglycerol; animal cell; animal experiment; animal model; animal tissue; Article; carbohydrate diet; controlled study; enzyme activation; enzyme phosphorylation; female; gene expression; lipid diet; lipid liver level; lipogenesis; liquid chromatography-mass spectrometry; liver cell; male; mouse; nonalcoholic fatty liver; nonhuman; obesity; oncogene src; priority journal; animal; C57BL mouse; cell culture; cytology; drug effect; lipogenesis; liver; metabolism; physiology; Animals; Cells, Cultured; Diglycerides; Female; Hepatocytes; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Receptors, Androgen
Type
journal article