Cyclin D1 regulates hepatic estrogen and androgen metabolism

Abstract

Cyclin D1 is a cell cycle control protein that plays an important role in regenerating liver and many types of cancer. Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner and thus may play an important role in hormone-responsive malignancies. In this study, we examine a distinct mechanism by which cyclin D1 regulates sex steroid signaling, via altered metabolism of these hormones at the tissue and cellular level. In male mouse liver, ectopic expression of cyclin D1 regulated genes involved in the synthesis and degradation of sex steroid hormones in a pattern that would predict increased estrogen and decreased androgen levels. Indeed, hepatic expression of cyclin D1 led to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression. Cyclin D1 also regulated the activity of several key enzymatic reactions in the liver, including increased oxidation of testosterone to androstenedione and decreased conversion of estradiol to estrone. Similar findings were seen in the setting of physiological cyclin D1 expression in regenerating liver. Knockdown of cyclin D1 in HuH7 cells produced reciprocal changes in steroid metabolism genes compared with cyclin D1 overexpression in mouse liver. In conclusion, these studies establish a novel link between the cell cycle machinery and sex steroid metabolism and provide a distinct mechanism by which cyclin D1 may regulate hormone signaling. Furthermore, these results suggest that increased cyclin D1 expression, which occurs in liver regeneration and liver diseases, may contribute to the feminization seen in these settings.

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

“…The liver transcriptome analysis suggested that the decreased serum TC was closely associated with the proliferation-related anabolism and cell cycle alteration. Estrogen promotes liver proliferation, and is closely related to the cell cycle alteration in liver (41,21), which establishes the closely association among them. As already reported (41), its inhibition broke the liver proliferation ( Figure 4B), further explaining why letrozole compromised the lipid-lowering effect of SAK-HV ( Figure 5), and verifying its role as a "starter" for liver proliferation.…”

“…Female hormone synthesis is involved in liver proliferation (21). SAK-HV promoted the synthesis of progesterone and estrogen in liver (Figure 3, D-F), which was significantly blocked by PGC-1α knockdown ( Figure 6, B-D).…”

“…Besides, liver is the main site for lowering serum TC. Steroid hormones, such as estrogen that is closely related to cell cycle alteration in liver (21), also play important roles in hepatic lipid metabolism (22,23). Therefore, we hypothesized that liver may be a target organ of SAK-HV.…”

Male Hypogonadism Causes Obesity Associated with Impairment of Hepatic Gluconeogenesis in Mice

“…These results suggest that male gonadal dysfunction may induce obesity with hyperlipidemia and hyperglycemia by affecting hepatic gluconeogenesis. Therefore, we analyzed the expression of major urinary protein 1 (MUP1), which is a typical androgen-responsive gene in mouse liver, 22,23) to confirm that the surgical castration had attenuated androgen activity in the liver. The level of MUP1 in the livers of Cast mice was significantly decreased compared with that in Sham mice (p<0.01; Fig.…”

Co-expression network analysis prioritizes signaling pathways regulating liver regeneration after partial hepatectomy in rats

“…Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner. Indeed, hepatic expression of cyclin D1 leads to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression in regenerating liver (Mullany et al, 2010). The "black" module containing 91 genes shows enrichment in tight junction assembly and cell cycle regulation.…”