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Molecular Biology

Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes

International Journal of Obesity volume 43, pages 2469–2479 (2019)Cite this article

Subjects

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.

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Acknowledgements

This study was supported by grants from the National Health Research Institutes, Taiwan (NHRI-EX104-10438SI), the Ministry of Science and Technology, Taiwan (MOST 107-2321-B-001-025, 107-3017-F-002-002), and “Center of Precision Medicine” from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (NTU-107L9014-1).

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Authors and Affiliations

  1. Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Ya-Wen Cheng, Kai-Wei Chen, Pei-Jer Chen & Shiou-Hwei Yeh

  2. The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, 100, Taiwan

    Han-Chun Kuo & Ching-Hua Kuo

  3. School of Pharmacy, National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Ching-Hua Kuo

  4. NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan

    Wei-Hsiang Lin, Pei-Jer Chen & Shiou-Hwei Yeh

  5. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Pei-Jer Chen

  6. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Pei-Jer Chen

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Cheng, YW., Chen, KW., Kuo, HC. et al. Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes. Int J Obes 43, 2469–2479 (2019). https://doi.org/10.1038/s41366-019-0431-z

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