Ya-Wen Cheng1, Kai-Wei Chen1, Han-Chun Kuo2, Ching-Hua Kuo2,3, Wei-Hsiang Lin4, Pei-Jer Chen1,4,5,6, Shiou-Hwei Yeh7,8. 1. Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan. 2. The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, 100, Taiwan. 3. School of Pharmacy, National Taiwan University College of Medicine, Taipei, 100, Taiwan. 4. NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan. 5. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan. 6. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan. 7. Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan. shyeh@ntu.edu.tw. 8. NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan. shyeh@ntu.edu.tw.
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.
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.
Authors: Christopher D Williams; Joel Stengel; Michael I Asike; Dawn M Torres; Janet Shaw; Maricela Contreras; Cristy L Landt; Stephen A Harrison Journal: Gastroenterology Date: 2010-09-19 Impact factor: 22.682