DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice

Abstract

Hyperandrogenemia (HA) is a hallmark of polycystic ovary syndrome (PCOS) and is an integral element of nonalcoholic fatty liver disease (NALFD) in females. Administering low dose dihydrotestosterone (DHT) induced a normal weight PCOS-like female mouse model displaying NAFLD. The molecular mechanism of HA-induced NAFLD has not been fully determined. We hypothesized that DHT would regulate hepatic lipid metabolism via increased SREBP1 expression leading to NAFLD. We extracted liver from control and low dose DHT female mice; and performed histological and biochemical lipid pro-files, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver compared to controls. However, DHT did not alter the levels of SREBP2 in the liver. DHT mice displayed increased SCAP protein expression and SCAP-SREBP1 binding compared to controls. DHT mice exhibited increased AR binding to intron-8 of SCAP leading to increased SCAP mRNA compared to controls. FAS mRNA and protein expression was increased in liver of DHT mice compared to controls. p-ACC levels were unaltered in liver. Other lipid metabolism pathways were examined in liver, but no changes were observed. Our findings support evidence that DHT increased de novo lipogenic proteins resulting in increased hepatic lipid content via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction was elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action may be increased AR binding to an ARE in SCAP intron-8.

The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications

“…The sex-specificity of this hormone was identified in this process. In this regard, although beneficial in males, excessive androgen impaired hepatic lipid metabolism and promoted hepatic steatosis in androgen-treated female rodents, as showed by Seidu et al in 2021 [139], which was similar to the results obtained in PCOS females (Figure 2).…”

Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

“…Androgen signaling and hepatic lipid metabolism. Many studies have shown that altered androgen levels impair lipid metabolism and cause hepatic steatosis in both humans and rodents [ 140 , 171 , 186 , 187 , 188 , 189 ], pointing to a role of androgen signaling in the regulation of lipid metabolism in the liver.…”

“…Although beneficial in males, androgen excess impairs hepatic lipid metabolism and promotes hepatic steatosis in androgen-treated female rodents [ 189 , 191 ], resembling what observed in PCOS women [ 169 ]. In female mice, DHT increases SCAP (sterol regulatory element-binding protein cleavage-activating protein) protein expression and SCAP-SREBP1 binding, thus favoring the nuclear localization of SREBP1 and promoting DNL [ 189 ].…”

“…Although the role of androgens in females has been less extensively investigated than in males, several reports indicate that high androgen levels trigger NAFLD development in females [ 140 , 189 , 191 , 423 , 424 ]. In normal weight female mice, DHT causes liver steatosis via transcriptional regulation of SCAP [ 189 ]. Androgen excess induces insulin resistance and NAFLD in PCOS women as well as in PCOS-like rodents [ 140 , 191 , 423 , 424 ].…”

Current Perspectives on Nonalcoholic Fatty Liver Disease in Women with Polycystic Ovary Syndrome

“…A low-dose dihydrotestosterone (DHT)-induced model of normal weight PCOS-like female mice with NAFLD showed that DHT enhanced the binding of an androgen receptor (AR) to an androgen response element (ARE) in sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP) intron 8, elevating the SCAP-SREBP1 interaction, leading to an increase in nuclear SREBP1, and resulting in increased hepatic adipose de novo synthesis. 42 According to the literature, PCOS-like rats with 12 weeks of induced DHT exposure showed that chronic androgen overload leads to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing apoptosis and autophagy imbalance. 43 In letrozole-induced PCOS-like rat models and DHT-treated HepG2 models, excess androgens cause steatosis by inhibiting the adenosine monophosphate (AMP)-activated protein kinase alpha pathway.…”