Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, being frequently associated with obesity, unbalanced dietary regimens, and reduced physical activity. Despite their greater adiposity and reduced physical activity, women show a lower risk of developing NAFLD in comparison to men, likely a consequence of a sex-specific regulation of liver metabolism. In the liver, sex differences in the uptake, synthesis, oxidation, deposition, and mobilization of lipids, as well as in the regulation of inflammation, are associated with differences in NAFLD prevalence and progression between men and women. Given the major role of sex hormones in driving hepatic sexual dimorphism, this review will focus on the role of sex hormones and their signaling in the regulation of hepatic metabolism and in the molecular mechanisms triggering NAFLD development and progression.

Keywords: NAFLD; androgen receptor; androgens; estrogen receptors; estrogens; liver; metabolism; sex and gender differences; sex hormones; sexual dimorphism.

Figure 1

Main factors contributing to the hepatic sexual dimorphism. Abbreviations: E2, 17β-estradiol; GH, growth hormone; T, testosterone.

Figure 2

Potential mechanisms of action through which estrogen and androgen receptors can exert their action in hepatocyte cells. Abbreviations: AP-1, activator protein-1; AR, androgen receptor; ARE, androgen responsive element; DHT, dihydrotestosterone; E2, 17β-estradiol; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERE, estrogen responsive element; GPER, G protein-coupled estrogen receptor; IGFR, insulin-like growth factor receptor; P, phosphorylation; Palm, palmitoylation; T, testosterone.

Figure 3

Main sex differences in the regulation of healthy liver accounting for sex differences in NAFLD susceptibility. Arrows represent the relative regulation between males (blue) and females (red). With respect to men, women display decreased visceral adipose tissue lipolysis, limited FA uptake and DNL, restrained lipid storage and inflammation and enhanced FAO and lipid secretion. Abbreviations: DNL, de novo lipogenesis; FA, fatty acids; FAO, fatty acids oxidation; FFA, free fatty acids; ROS, reactive oxygen species; TG, triglycerides; VLDL-TG, very-low density lipoproteins—triglycerides; WAT, white adipose tissue.

Figure 4

Main risk factors for NAFLD development in men and women. For both sexes, obesity, unbalanced dietary regimens and reduced physical activity represent risk factors for NAFLD development and progression. Arrows represent the relative regulation between males (blue) and females (red). Compared to men, obese pre-menopausal women display more subcutaneous than visceral fat and higher insulin sensitivity, leading to reduced adipose tissue lipolysis and FFA delivery to liver; women show limited HGP and DNL. Under an excess of dietary sugars and fats, with respect to men, women have higher insulin sensitivity, inhibit hepatic lipid uptake, HGP and DNL, and promote FAO and lipid export. Although generally women have a lower physical activity than men, when exercised, oxidize more fats due to the increased type I muscle fibers. Abbreviations: DNL, de novo lipogenesis; FAO, fatty acids oxidation; FFA, free fatty acids; HGP, hepatic glucose production.

Figure 5

Consequences of altered estrogen signaling in the liver of males (left, in blue) and females (right, in red) favoring NAFLD development and progression. Abbreviations: AA, amino acids; Acaca, acetyl-CoA carboxylase α; Acadm, acyl-CoA dehydrogenase medium chain; Acly, ATP citrate lyase; Adrp, adipocyte differentiated regulatory protein; ApoB; apolipoprotein B; Cat, catalase; CH, cholesterol; CYP19A1, aromatase; DNL, de novo lipogenesis; Elovl6, ELOVL fatty acid elongase 6; ERαKO, total ERα knockout mice; FA, fatty acids; FAO, fatty acid oxidation; Fasn, fatty acid synthase; Fgf21, fibroblast growth factor 21; G6pc, glucose-6-phosphatase; GNG, gluconeogenesis; HFD, high fat diet; HGP, hepatic glucose production; Hmgcr, 3-hydroxy-3-methylglutaryl-CoA reductase; Il-1β, interleukin 1β; Il-6, interleukin 6; Il-12β, interleukin 12β; LERKO, liver ERα knockout mice; MTTP; microsomal triglyceride transfer protein; OVX, ovariectomy; Pck1, phosphoenolpyruvate carboxykinase 1; Pmvk, phosphomevalonate kinase; Pparα, peroxisome proliferator activated receptor α; Scd1, stearoyl-CoA desaturase 1; Srebp1c, sterol regulatory element binding Transcription factor 1; Tnfα, tumor necrosis factor α; VLDL-TG, very-low density lipoprotein-triglycerides; WAT, white adipose tissue.

Figure 6

Consequences of altered androgen signaling in the liver of males (left, in blue) and females (right, in red) favoring NAFLD development and progression. Low and high androgen levels are detrimental for the hepatic health of males and females, respectively. Abbreviations: Acaca, acetyl-CoA carboxylase α; AMPK, AMP-activated protein kinase; ApoB; apolipoprotein B; ARKO, total AR knockout mice; Cpt1α, carnitine palmitotyltransferase 1; DHT, dihydrotestosterone; DNL, de novo lipogenesis; FAO, fatty acid oxidation; Fasn, fatty acid synthase; Foxo1, forkhead transcription factor 1; G6pc, glucose-6-phosphatase; GNG, gluconeogenesis; HGP, hepatic glucose production; Il-1β, interleukin 1β; Il-6, interleukin 6; JNK, c-Jun N-terminal kinase; LARKO, liver AR knockout mice; MTTP; microsomal triglyceride transfer protein; NF-𝜅B, nuclear factor-𝜅B; ORX, orchidectomy; Pck1, phosphoenolpyruvate carboxykinase 1; PCOS, poly-cystic ovary syndrome; Pgc1α, peroxisome proliferator-activated receptor-γ coactivator-1α; Pparα, peroxisome proliferator activated receptor α; Pparγ, peroxisome proliferator activated receptor γ; Scap, sterol regulatory element-binding protein cleavage-activating protein; Srebp1c, sterol regulatory element binding Transcription factor 1; T, testosterone; Tnfα, tumor necrosis factor α.

Figure 7

Sex-specific relevance of estrogens and androgens in the regulation of lipid metabolism in the liver of males and females accounting for differences in NAFLD susceptibility. In male liver, androgens and low levels of testosterone-derived estrogens partly limit lipid deposition by inhibiting adipose tissue lipolysis, FA uptake, and DNL, and by promoting FAO and lipid export. In female liver, estrogens prevent while high levels of androgens (especially DHT) promote lipid deposition, by differentially regulating adipose tissue lipolysis, FA uptake, DNL, FAO and lipid export. Abbreviations: DHT, dihydrotestosterone; DNL, de novo lipogenesis; E2, 17β-estradiol; FA, fatty acids; FAO, fatty acid oxidation; T, testosterone.