Clinical Impact of Sexual Dimorphism in Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

Patrizia Burra; Debora Bizzaro; Anna Gonta; Sarah Shalaby; Martina Gambato; Maria Cristina Morelli; Silvia Trapani; Annarosa Floreani; Fabio Marra; Maurizia Rossana Brunetto; Gloria Taliani; Erica Villa


Liver International. 2021;41(8):1713-173. 

In This Article


NAFLD is a multi-factorial disease where a predisposed genetic background is under the negative influence of a number of environmental and lifestyle-related factors.[62] In the presence of a positive calorie balance and unfavourable genetic pattern, free fatty acids (FAs) accumulate in 'ectopic' tissues, including the liver,[63] resulting in accumulation of fat droplets in hepatocytes. Excessive fat within the liver is associated with different degrees of lipotoxicity,[64] which triggers a multicellular response to damage, leading to the development of inflammation, fibrosis and eventually cirrhosis. This process is modulated by signals deriving from extrahepatic tissues, such as the adipose tissue, the intestine and possibly the skeletal muscle.[64,65] The differences in pathogenesis based on sex are summarized in Figure 1 and are discussed in details below.

Figure 1.

Potential differences in the pathogenesis of NAFLD based on sex. Different levels of interactions, including intrahepatic mechanisms and extrahepatic factors are shown. For a detailed discussion and references, please refer to text. ♀ female sex ♂ male sex

Fat Accumulation and Lipotoxicity

The different pattern of fat accumulation in women (gynoid obesity) is associated with reduced risk of metabolic complications.[66] This may be due to the lower lipolytic response of peripheral adipocytes[67] and to the effects of oestrogens, which improve sensitivity to insulin, thus reducing lipolysis and the resulting disposal of fat to the liver.[68] Conversely, androgens levels in women are associated with visceral accumulation of fat and a higher metabolic risk.[69] The expression of genes involved in this pathway is reduced by oestrogens.[70] However, in humans fed a high fructose diet, induction of de novo lipogenesis (DNL) was more evident in women than in men,[71] and ALT were found to increase to a greater extent in males than in fertile women administered fructose.[72] Pre-menopausal women were protected from fructose-induced hypertriglyceridaemia because of a lower stimulation of DNL and a lower suppression of lipid oxidation.[73] It is interesting to observe that lipid composition also appears to differ according to sex, pointing to qualitative modifications accompanying possible quantitative changes. In fact, in the liver of ob/ob mice, FA profiles differed between sexes, with longer chain FAs and triglycerides in males. It is of note that lipotoxic FAs were more abundant in males than in females.[74] Hepatic accumulation of fat is also regulated by the metabolic effects of skeletal muscle, which is less sensitive to insulin in males.[75] Testosterone promotes protein synthesis and muscular regeneration, while oestrogens attenuate inflammation.[76] Moreover, oestrogen replacement therapy in post-menopausal women has beneficial effects on sarcopenia and fat accumulation.[77]


Toxic lipids can cause cell injury through oxidative stress, mitochondrial dysfunction, induction of cell death and inflammation, by innate immunity involvement.[78] In addition, changes in macrophage polarization have been linked to different NAFLD phenotypes, influenced by sex differences,[79] as reflected by the expression of receptors for androgens and oestrogens in macrophages, and the fact that androgens promote polarization towards an M2 phenotype.[80] There are also sex-dependent differences in macrophage expression of the pattern recognition receptor, TLR-4, and in activation of downstream signalling.[81] In general, the ability of macrophages to mount a detrimental inflammatory response is greater in males, at least in rodent models.[3]

Adipose Tissue Dysfunction

Adipose tissue is not only the source of free FAs that contribute to generating hepatic triglyceride accumulation, but also of a number of proteins, collectively known as adipokines (ADK), which act at distant sites regulating metabolic functions, inflammation and tissue repair.[82] Leptin amplifies inflammation and drives profibrogenic functions; adiponectin promotes insulin sensitivity and dampens inflammation and fibrosis. Secretion of ADK is markedly different in males and females,[83] and in general, ADK levels are higher in the latter. Increased resistance to leptin in females may be an additional mechanism underlying higher levels of this ADK,[84] although whether this translates into a different regulation of the hepatic response to fat accumulation is uncertain. Prohibitin has been shown to play a role in sex differences in adipose tissue functions, possibly regulating the sex differences in many pathophysiological conditions, such as obesity, IR and metabolic dysregulation.[85]

Gut Microbiota

Dysbiosis defines quantitative and qualitative changes of gut microbiota composition, and has been associated with development of metabolic abnormalities, NAFLD and cirrhosis.[64] Alteration in gut microbiota may contribute to NAFLD directly, via products of bacteria metabolism, or increasing the extraction of calories from food. Increased gut permeability associated with dysbiosis participates in the pathogenesis of chronic low-grade inflammation and result in activation of toll-like receptor such as TLR-4 in the liver, triggering pathways implicated in progression of liver diseases, including NAFLD. In addition, microbiota modulates FXR activation in the intestine, and the resulting secretion of FGF 15/19.[64] Heterogeneity in microbiota composition according to sex has been demonstrated[86] and could contribute to confer a different cardiovascular risk.[87] A recent study, indeed, demonstrated that the relationship between gut microbiota and metabolic disease seems to be sex-dependent and this might determine the differences in the predisposition to develop the MS between women and men.[64] According to these data, a possible impact on the pathogenesis of metabolic-induced liver diseases is likely.[79] Menopausal status is an additional factor influencing the microbiota.[88] Along these lines, the profile of bile acids in mice differs based on sex and age.[89]