Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice

Abstract

BACKGROUNDTreatment with estrogen in early menopausal women protects against development of hepatic steatosis and NAFLD but estrogen has undesirable side effects which negate its beneficial effects in pre- and post-menopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. ERα is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: 1) inducing gene transcription by direct binding to specific DNA sequences 2) inducing tethered transcription with other DNA binding factors 3) stimulating nongenomic action through membrane associated ERα. However, it is still unclear which mechanisms mediate ERα dependent protection against hepatic steatosis.METHODSTo understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA binding domain mutant mouse (KIKO), and liver-specific ERα knockout mouse (LERKO) fed high fat diets (HFD). The KIKO mouse disrupts the direct DNA binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum ALT levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis.RESULTSLiver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed WT controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls which correlated with increased serum testosterone levels.CONCLUSIONSERα mediated direct transcription in non-hepatic tissues is essential for estrogen mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.

Hepatic mitochondrial adaptations to physical activity: impact of sexual dimorphism, PGC1α and BNIP3‐mediated mitophagy

“…Previous literature showed that female mice are more resistant to diet‐induced hepatic steatosis (Hart‐Unger et al . ; Reue, ), suggesting that females may possess differences in hepatic metabolism (mitochondrial content, respiratory capacity or turnover). In addition, the demands of gestation and lactation have likely led to evolutionary differences in the capacity for hepatic mitochondria to adapt differently from those of males (Maggi & Della Torre, ).…”

“…As previous evidence suggests that female mice may be protected from diet‐induced metabolic dysfunction in the liver (Hart‐Unger et al . ; Reue, ), we also chose to test if males or females displayed differential hepatic mitochondrial adaptations to physical activity in each genotype. An illustrated representation of the experimental purpose and design is shown in Fig.…”

“…Finally, because females are known to display greater lipid oxidation during exercise (Hedrington & Davis, ) and are known to be protected from steatosis (Hart‐Unger et al . ; Reue, ) we hypothesized that female mice would display greater physical activity‐induced changes in maximal mitochondrial respiratory capacity, ETS protein content and mitophagy compared to male counterparts.…”

Identification of hepatic fibroblast growth factor 21 as a mediator in 17β‐estradiol‐induced white adipose tissue browning

“…Notably, estrogens are primarily metabolized in the liver via hydroxylation by cytochrome P450 enzymes. Estrogen receptor a (ERa) is abundantly expression in the liver (9,10), and recent studies have revealed that the transcriptional activity of hepatic ERa is strictly associated with the reproductive cycle (6) and nutritional status (11) and have a profound influence on liver lipid metabolism (12). These reports reveal that the liver is an important target organ for estrogen.…”

Sex differences in the regulation of hepatic mitochondrial turnover following physical activity: do males need more quality control than females?

“…They also hypothesized that females would demonstrate larger increases in respiratory capacity, given their greater reliance on fat oxidation and apparent protection from steatosis, at least in rats (Hart‐Unger et al . ).…”