Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) increases in males aged >45 years, which indicates that androgens are associated with the development and/or progression of NAFLD, although excess dietary intake is the primary causative factor. However, it is uncertain how androgens are involved in the metabolic process of NAFLD, which is associated with the state of steatosis in hepatocytes. To investigate whether androgen receptor (AR) signaling influences NAFLD development, the state of steatosis was monitored in mouse livers and hepatocytes with or without androgens. As a result, hepatic lipid droplets, expression of AR, and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) increased in the presence of testosterone. Concurrently, the expression of LKB1, an upstream regulator of AMPK, was increased by testosterone treatment. We observed that the fluctuation of AMPK-ACC signaling, which plays an important role in lipogenesis, depends on the presence of testosterone and AR. Additionally, we demonstrated that testosterone bound AR was recruited to the promoter of the LKB1 gene and induced LKB1 expression. Our study highlights a novel mechanism by which testosterone modulates NAFLD development by inducing the mRNA expression of LKB1.
Highlights
To determine whether hepatic TG accumulation depends on the levels of androgens, male mice were subjected to surgical castration and were injected with 2.5 mg/mL testosterone (T) every 3 days
We divided the mice into the normal diet group (ND) and the high-fat diet group (HD) to confirm whether androgens participate in lipid metabolism (Figure 1A)
When we quantified the area of the lipid droplets stained with Oil Red O, a defined increase was observed in the HD group compared to the ND group
Summary
Non-alcoholic fatty liver disease (NAFLD) refers to the state of steatosis, which is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes, regardless of alcohol assumption [1,2]. NAFLD is distinguished from non-alcoholic steatohepatitis (NASH) by the presence of inflammation. NASH, which is accompanied by inflammation, is a more advanced form than NAFLD and can progress to cirrhosis and liver cancer as hepatocarcinoma [3,4]. NAFLD must be managed to prevent progression to NASH or beyond. Obesity is a representative risk factor related to the incidence of NAFLD [5]. This is attributed to the promotion of hepatic de novo lipogenesis (DNL), when the excess energy intake, composed of carbohydrates and/or fat, is met [6].
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