NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

Keywords: Fibrosis; Hormones; Inflammation; Man; Menarche; Menopausal status; NASH; Physiopathology; Sex; Steatosis; Women.

Fig. 1

Physiopathological grounds accounting for male sex as a strong predictor of NAFLD. Male gender and menopausal status have been associated with the risk of NAFLD independently of age and metabolic factors in cross-sectional studies. On the basis of human studies and extrapolation of notions from animal studies, it can be speculated that female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than VLDL-TAG [23], and to sex-specific browning of white adipose tissue which contributes in protecting female mice from experimental NAFLD associated with methionine choline deficient diet [24]. However, after menopause women display a similar or even higher prevalence of NAFLD compared to men, supporting a protective effect of estrogens. Finally, risk factors associated with NAFLD development are different in men compared to women. TAG triacylglycerols, WAT white adipose tissue

Fig. 2

Hormonal changes are a major determinant of progressive NAFLD in human menopause. NAFLD epidemiology and physiopathology are modulated by age at menarche and postmenopausal status. For example, early menarche may confer an increased risk of NAFLD in adulthood partly mediated by excess adiposity [130, 131, 133]. Moreover, ovarian senescence, via estrogen deficiency, may eventually be conducive to both massive liver steatosis and its fibrotic evolution via dysmetabolic traits including T2D, hypertriglyceridemia, and visceral obesity which are often found postmenopausally [29, 81, 135]