Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

Abstract

There is extensive evidence supporting the interplay between metabolism and immune response, that have evolved in close relationship, sharing regulatory molecules and signaling systems, to support biological functions. Nowadays, the disruption of this interaction in the context of obesity and overnutrition underlies the increasing incidence of many inflammatory-based metabolic diseases, even in a sex-specific fashion. During evolution, the interplay between metabolism and reproduction has reached a degree of complexity particularly high in female mammals, likely to ensure reproduction only under favorable conditions. Several factors may account for differences in the incidence and progression of inflammatory-based metabolic diseases between females and males, thus contributing to age-related disease development and difference in life expectancy between the two sexes. Among these factors, estrogens, acting mainly through Estrogen Receptors (ERs), have been reported to regulate several metabolic pathways and inflammatory processes particularly in the liver, the metabolic organ showing the highest degree of sexual dimorphism. This review aims to investigate on the interaction between metabolism and inflammation in the liver, focusing on the relevance of estrogen signaling in counteracting the development and progression of non-alcoholic fatty liver disease (NAFLD), a canonical example of metabolic inflammatory-based liver disease showing a sex-specific prevalence. Understanding the role of estrogens/ERs in the regulation of hepatic metabolism and inflammation may provide the basis for the development of sex-specific therapeutic strategies for the management of such an inflammatory-based metabolic disease and its cardio-metabolic consequences.

Characterization of the CDAA Diet-Induced Non-alcoholic Steatohepatitis Model: Sex-Specific Differences in Inflammation, Fibrosis, and Cholesterol Metabolism in Middle-Aged Mice

“…The prevalence of NAFLD is higher in men than it is in women of reproductive age; however, following menopause, this sex difference is reduced or abolished ( Gutierrez-Grobe et al, 2010 ), this age-dependent disparity between the sexes likely results from hormonal changes in women occurring as a result of menopause ( Della Torre, 2020 ). In premenopausal women, hepatic metabolism and inflammation are under the control of sex hormones and serve reproductive needs ( Della Torre et al, 2014 ).…”

The Association Between Different Obesity Phenotypes and Liver Fibrosis Scores in Elderly Individuals with Fatty Liver in Taiwan

“… 49 Estrogen is believed to have antioxidant and antisteatotic effects in the liver through sensitization of Kupffer cells to toxic stimuli and in driving the anti-inflammatory polarization of Kupffer cells. 50 , 51 Perhaps loss of estrogen’s protective role in NAFLD may contribute to fibrotic progression in postmenopausal women. In addition, women’s adipose tissue distribution changes as estrogen declines in the elderly, shifting from gluteal-femoral area to abdominal region after menopause.…”

Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…Meanwhile, E2 treatment promoted fatty-acid oxidation in the liver by increasing the expression of the fatty-acid transport protein, carnitine palmitoyltransferase 1 (CPT-1) [ 34 ]. In ovariectomized (OVX) female mice, estrogen replacement improves insulin sensitivity and facilitates the VLDL-mediated export of lipids from the liver by increasing hepatic VLDL-TG production [ 74 ]. Interestingly, long-term therapy of tamoxifen, a selective estrogen receptor modulator, can increase the risk of NAFLD in breast cancer patients [ 75 ].…”