Liver Androgen Receptor Knockout Improved High-fat Diet Induced Glucose Dysregulation in Female Mice But Not Male Mice.

Previous research has indicated that liver androgen receptors may play a role in modulating disease. This study aims to investigate the pathophysiology of high-fat diet (HFD) induced dysglycemia in male and female liver androgen receptor knockout (LivARKO) mice. We performed metabolic tests on LivARKO female and male mice fed a HFD or a control diet (from Research Diets Inc.) during months 1 or 2 after starting the diet. Additionally, we performed Western blot and quantitative real-time PCR analysis on the livers of the mice to examine intermediates in the insulin signaling pathway. LivARKO-HFD female mice displayed no difference in glucose tolerance compared to female LivARKO-Control (Con) mice, whereas in wild-type female mice, HFD impaired glucose tolerance (IGT). Our data suggests that starting at 1 month, LivARKO may be protecting female mice from HFD-induced metabolic dysfunction. LivARKO-HFD female mice displayed significantly worse insulin sensitivity at 15 minutes compared to LivARKO-Con female mice, but, strangely, LivARKO-HFD female mice had significantly better insulin sensitivity at 60 and 90 minutes compared to LivARKO-Con female mice. Despite protecting against IGT, LivARKO did not protect against HFD-induced hyperinsulinemia in female mice. In contrast to females, male LivARKO-HFD mice displayed impaired glucose tolerance compared to male LivARKO-Con mice. Thus, LivARKO is not protective against HFD-induced glucose metabolic dysfunction in male mice. Lastly, LivARKO-HFD female mice maintained hepatic insulin sensitivity whereas LivARKO-HFD male mice displayed hepatic insulin resistance. These findings suggest that LivARKO delayed the onset of HFD-induced dysglycemia in female mice.

Nonalcoholic Fatty Liver Disease in Women and Girls With Polycystic Ovary Syndrome.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of liver damage due to excessive hepatic lipid accumulation. Recent research has demonstrated a high prevalence of NAFLD in women with polycystic ovary syndrome (PCOS). RESULTS: Strong associations independent of body mass index (BMI) have been found between high androgen levels characteristic of PCOS, as well as insulin resistance, and the presence of NAFLD in these women, suggesting that these factors contribute to liver injury more significantly than obesity. Current studies indicate the occurrence of NAFLD in normal weight women with PCOS in addition to the commonly researched women who are overweight and obese. While the majority of studies address NAFLD in adult, premenopausal women (ages 25-40 years), the occurrence of NAFLD in young and adolescent women has gone largely unaddressed. Research in this field lacks diversity; a majority of studies either focus on populations of White women or are missing demographic information entirely. CONCLUSIONS: Future studies should include larger, more racially and ethnically inclusive populations and particular attention should be paid to how excess androgens and insulin resistance contribute to the increased risk of NAFLD seen in women with PCOS of varying weights, ages, and ethnicities. OBJECTIVE AND METHODS: Here, we review NAFLD in women with PCOS with subsections focused on the impact of hyperandrogenism, BMI, insulin resistance and age. Most notably, we present the most up-to-date racially and ethnically diverse worldwide prevalence of NAFLD in women with PCOS compared with women without PCOS (51.56% vs 29.64%, P < .001, respectively).

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

Hyperandrogenemia (HA) is a hallmark of polycystic ovary syndrome (PCOS) and is an integral element of non-alcoholic 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 profiles, 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 the liver of DHT mice compared to controls. p-ACC levels were unaltered in the liver. Other lipid metabolism pathways were examined in the 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 the 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.