Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

Abstract

The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.

Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease

“…Conversely, the results of a retrospective study suggest that the excess androgens present in women with polycystic ovary syndrome render them more likely to develop NAFLD 94 . Clinical trials of antiandrogen treatment in patients with HCC have failed to show any benefit, but were mostly carried out in patients with late-stage, virally induced tumours 95 .…”

Risk Factors of Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

“…Both estrogen and androgen are steroid hormones that mediate their action by binding to nuclear receptors and acting as transcription factors to regulate the expression of multiple genes. Progression from hyperplasia to HCC may be associated with suppression of estrogen receptors and elevated AR expression 41,42 .…”

Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…Similar results were confirmed in hepatic AR-deficient mice, indicating that AR might play a role in the suppression of NAFLD [ 76 , 86 ]. Indeed, androgen/AR signaling was revealed to suppress fatty-acid synthesis by decreasing the expression of sterol regulatory element-binding protein (SREBP) and to induce insulin sensitivity by modulating phosphoinositide-3 kinase activity [ 24 ].…”

“…Activation of the renin–angiotensin–aldosterone system modulated by multiple steroid hormones and corresponding receptors causes liver inflammation and fibrosis [ 22 , 23 ]. Moreover, steroid hormone receptor-regulated target genes are involved in both cholesterol and fatty-acid metabolism [ 24 ] and, therefore, have been implicated in the pathogenesis of NAFLD.…”