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.

Keywords: NAFLD (non-alcoholic fatty liver disease); estrogen receptors; estrogens; liver; sex differences.

Figure 1

Overview of estrogen action through ERα, ERβ and GPER in counteracting NAFLD development and progression in women. Estrogens favor fat distributionr to subcutaneous deposits, inhibit adipose tissue lipolysis and reduce the uptake of FFAs, thus limiting the flux of FFAs to the liver. Estrogens limit dietary-induced DNL and facilitate the export of lipids as VLDL-TG. Estrogens promote the FA β-oxidation and prevent the activation of a sustained alternative FA oxidation that triggers lipotoxicity and the generation of ROS that, in turn, activate a pro-inflammatory response. Hepatocellular damage and fat-derived factors mediate the local activation of a pro-inflammatory response by hepatocytes, KCs and HSCs, that promote the degeneration of hepatic tissue and the recruitment of extra-hepatic immune cells that boost the inflammatory response and worsen the metabolic alterations. DNL, de novo lipogenesis; E2, estrogens (mainly 17β-estradiol); FAs, fatty acids; FFAs, free fatty acids; FAO, fatty acid oxidation; Hep, hepatocytes; HSCs, hepatic stellate cells; KCs, Kupffer cells; ROS, reactive oxygen species; TG, triglycerides; VLDL, very-low density lipoprotein.