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Androgen receptor functions in pericentral hepatocytes to decrease gluconeogenesis and avoid hyperglycemia and

Kai-Wei Chen1, Yu-Shan Chen1, Pei-Jer Chen2

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Metabolism: Clinical and Experimental
|August 1, 2022
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Summary

Hepatic androgen receptor (AR) plays a key role in liver metabolism, reducing blood glucose and body weight. Stabilizing hepatic AR may offer a new strategy for preventing hyperglycemia, obesity, and nonalcoholic fatty liver disease (NAFLD) in males.

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Area of Science:

  • Hepatology
  • Endocrinology
  • Metabolic Research

Background:

  • The physiological role of the hepatic androgen receptor (AR) pathway in normal liver function remains unclear despite its known impact on liver pathogenesis.
  • This study investigates the function of hepatic AR in liver metabolism, a primary function of the liver.

Purpose of the Study:

  • To determine if hepatic androgen receptor (AR) influences liver metabolism.
  • To elucidate the role of hepatic AR in regulating glucose and lipid metabolism in mice.

Main Methods:

  • Established albumin promoter-driven hepatic-specific AR-transgenic (H-ARTG) mice, alongside wild-type (WT) and hepatic AR knockout (H-ARKO) mice.
  • Compared body weight, metabolic parameters, and tolerance tests in H-ARTG, WT, and H-ARKO mice fed a chow diet from 2 to 18 months.
  • Investigated AR expression and localization in response to feeding and insulin stimulation.

Main Results:

  • H-ARTG mice exhibited 15% lower body weight, reduced blood glucose, and lower liver triglyceride levels compared to WT mice.
  • Activated hepatic AR was found to decrease gluconeogenesis and liver triglyceride levels, with opposite phenotypes observed in H-ARKO and castrated H-ARTG mice.
  • Hepatic AR enhances cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) expression, reducing gluconeogenesis from glycerol, and is expressed in zone 3 hepatocytes, with levels fluctuating based on glucose demand.

Conclusions:

  • Hepatic androgen receptor (AR) is a newly identified zone 3 hepatic gene that reduces blood glucose and body weight in mice.
  • Stabilization of hepatic AR presents a potential therapeutic strategy for managing hyperglycemia, obesity, and nonalcoholic fatty liver disease (NAFLD) in males.