Nonalcoholic Fatty Liver Disease in Polycystic Ovary Syndrome: A Race Against the Clock

In parallel with increasing obesity rates reported on a global scale, nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that is also rising in prevalence in both sexes. NAFLD is characterized by lipid accumulation in the liver and encompasses pathologies of NAFL and nonalcoholic steatohepatitis, which can progress to hepatic inflammation, fibrosis, and injury (1). The current global prevalence of NAFLD is approximately 24%; moreover, along with an expected rise in its incidence are comorbidities resulting from nonalcoholic steatohepatitis (2). Trends in mortality of NAFLD indicate that women are experiencing more steeply inclining rates, and these mortalities are more often attributed to cirrhosis in women than in men (2), which highlights the necessity of its management.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, affecting between 5% to 20% of women. Throughout a woman's life, PCOS may contribute to a number of associated organ-specific ailments and dysfunctions across systems of the body. Hyperandrogenemia is a key clinical feature of PCOS, along with ovulatory dysfunction and polycystic ovary morphology; hyperandrogenemia is associated with the most severe phenotypes of the syndrome (3). Women with PCOS are at higher risk for developing several cardiometabolic comorbidities including type 2 diabetes, hypertension, obesity, and insulin resistance (4, 5). Importantly, there is increasing recognition of NAFLD development associated with PCOS, and the 2 diseases share many of the same comorbidities. In a meta-analysis of 17 different studies, women with PCOS were found to have a 2.5 times higher risk for the development of NAFLD. Even adjusting for relevant cofactors, including body mass index, age, and circulating lipids, the free-androgen index is an independent risk factor for NAFLD in women with PCOS (1). Interestingly, sex hormone–binding globulin, which is generally lower in PCOS thus increasing free testosterone, may be protective against NAFLD development by modulation of hepatic lipogenesis (6). Identification of individuals at higher risk for NAFLD within the PCOS population and elucidation of androgen-mediated mechanisms of steatohepatitis development are critically needed areas of research.

In their recent publication (7), Roy et al evaluated the molecular, cellular, and (patho)physiological actions of hyperandrogenemia on hepatic steatosis. They developed a novel hepatocyte-specific androgen receptor (AR) knockout mouse model to study the direct action of hyperandrogenemia in the liver in PCOS. Using a well-established female mouse model of peripubertal androgen excess exposure that closely resembles endocrine and metabolic features of PCOS, they showed that hepatocyte-specific AR genetic ablation prevents hyperandrogenemia-mediated weight gain, hyperglycemia, and hepatic steatosis and triglyceride accumulation. State-of-the-art transcriptome analysis showed that hyperandrogenemia regulates the expression of multiple genes involved in liver metabolism by the direct binding of the AR to the promoter of those genes. These findings help explain the liver metabolism dysregulation and steatosis observed in PCOS as well as highlight that the liver is a direct target of hyperandrogenemia, although it is still possible that other dysregulated organs involved in metabolism (adipose tissue, skeletal muscle, brain, etc) may also affect liver function in PCOS.

Roy and colleagues’ (7) detailed gene ontology analysis of the hyperandrogenemia-regulated hepatic transcriptome revealed that multiple circadian clock genes are regulated in this PCOS model. Moreover, the authors showed how circadian clock genes such as Bmal1 (brain and muscle Arntl-like1) bind to the promoter and regulate the expression of genes involved in liver metabolism such as Mogat1 (monoacylglycerol acyltransferase), which contributes to hepatic glyceride pools. Surprisingly, when the authors tried to prove that androgen-bound AR binds to the promoter and regulates the expression of circadian clock genes such as Bmal1, the results were inconclusive, suggesting a more complex regulatory circuit. To decipher AR-mediated Bmal1 regulation, Roy et al (7) performed subsequent studies that showed androgens regulate hepatic circadian clock gene expression by a double-pronged epigenetic mechanism that regulates circadian clock gene promoter-bound histone H3 methylation status. The authors showed that hyperandrogenemia specifically decreases the trimethylation of lysine 27 on histone 3 (H3K27me3), a gene-silencing mark, on the promoter region of the circadian clock gene Bmal1. The decrease in Bmal1 promoter-bound H3K27me3 is achieved by 2 concurrent mechanisms: (1) increased microRNA-101 expression, which in turn decreased the protein levels of the histone methyltransferase Ezh2 (enhancer of zeste homologue 2), and (2) increased expression of the histone demethylase Jmjd3 (Jumonji domain–containing protein-3). Both mechanisms lead to a decrease in Bmal1 promoter-bound gene-silencing mark H3K27me3 to in turn increase circadian clock gene expression and ultimately modulate hepatic metabolism. This intriguing and complex mechanism of hepatic metabolism regulation in PCOS elucidated by Roy et al (7) allows us to reflect on how much more understanding of PCOS pathology is needed to better help patients affected by this syndrome.

Both central and peripheral circadian clocks have been involved in multiple physiological and pathological states. Specifically in the liver, the circadian clock regulates metabolic gene expression and, consequently, organ and whole-body metabolism. Oscillations in clock activator and repressor proteins modulate clock-controlled gene expression. Cyclically expressed clock-controlled genes include rate-limiting enzymes responsible for metabolic processes, in addition to transcription factors that themselves serve to coordinate key metabolic pathways. Imbalances in central and peripheral, including hepatic, circadian rhythms can negatively affect health and metabolism. Clinical studies of obese young women with PCOS have shown that there is a morning circadian misalignment that is associated with insulin resistance and serum testosterone (8). That aforementioned study complements other ones that have shown that women with PCOS have overall poorer sleep health, suggesting a critical association between circulating androgens and circadian misalignment in women affected by PCOS. The mounting evidence on the interrelation between circadian rhythm and (patho)physiology in general, but also metabolism in particular, highlights the timely importance of the study by Roy et al (7). Additionally, further explanation of androgen-mediated dysregulation of lipid storage and processing provides insight into 2 overlapping, prevalent diseases such as NAFLD and PCOS. Groundbreaking studies such as the one by Roy et al (7) illuminate new research questions that will certainly stimulate many to embrace the exciting field of circadian regulation of metabolism in PCOS.

Abbreviations

AR

androgen receptor

NAFLD

nonalcoholic fatty liver disease

PCOS

polycystic ovary syndrome

Financial Support

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (award No. P20GM121334). A.M.H. was supported by American Heart Association Predoctoral Fellowship 903804. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosures

The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article as no data sets were generated or analyzed during the present study.