Macrophages in the pathophysiology of NAFLD: the role of sex differences

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial pathological condition, which recognizes a certain sexual dimorphism. Experimental and clinical studies provided evidence for a critical role of macrophages in NAFLD development and progression. Especially liver resident macrophages (also known as Kupffer cells) are likely the common final pathway of several pro-steatosic signals. A huge amount of danger-associated molecular patterns recognized by Kupffer cells is provided within the liver by lipid and glucose toxicity. Other pro-inflammatory signals come from surrounding tissues into the portal vein, directly to the liver: they come from dysfunctional adipocytes, adipose tissue macrophages and gut dysbiosis. These complex cross-talks are differently represented across sexes, as sexual hormones control many of these processes. Sexual dimorphism then modulates metabolic and inflammatory cascades driving the liver from a simple steatosis to NAFLD and beyond. Here, metabolic and inflammatory mechanisms underlying NALFD pathophysiology will be updated. A special attention will be paid to describe sex-related differences that could provide insights for patient stratification and more tailored therapeutic approaches.