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Abstract
BackgroundThe prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.ObjectivesWe aimed to assess sex-specific differences in the expression of inflammatory and fibrotic genes, as well as in cholesterol metabolism, focusing on the expression of Pcsk9 in several tissues in a mouse model of NASH that shows the typical features of the human condition.Methods and ResultsWe fed 10-months-old male and female C57Bl/6J mice with a NASH-inducing CDAA or corresponding control diet for 8 weeks. We found that, compared to the control male mice baseline, hepatic Pcsk9 expression as well as serum PCSK9 level was significantly higher in females, and both circulating PCSK9 level and the hepatic Pcsk9 gene were markedly decreased in female mice during NASH development. Histological analysis revealed that male and female mice develop a similar degree of steatosis; however, fibrosis was more pronounced in males upon CDAA diet feeding. Strikingly, female mice have higher hepatic expression of the pro-inflammatory cytokines (Il1b, Ifng), and increased IL-1β cleavage by the NLRP3 inflammasome, and a decrease in Clec4f+ resident Kupffer cell population in comparison to males in the CDAA-fed groups.ConclusionThis is the first demonstration that there are critical sex-specific differences during NASH development in middle-aged mice regarding inflammation, fibrosis, and cholesterol metabolism and that changes in PCSK9 and IL-1β are likely important contributors to sex-specific changes during the transition to NASH.
Highlights
Non-alcoholic fatty liver diseases (NAFLD) and subsequent non-alcoholic steatohepatitis (NASH) are becoming the most significant causes of liver disease worldwide, without any approved drugs for their treatment
Eight weeks of the Choline Deficient L-Amino Acid defined (CDAA) diet in 10-month-old male and female mice led to the typical morphological features of steatohepatitis (Figure 2)
Eight weeks of the CDAA diet did not lead to significant differences in body weight (Figure 2C), making this model an excellent tool to investigate the direct effect of NASH without the confounding effects of body weight gain
Summary
Non-alcoholic fatty liver diseases (NAFLD) and subsequent non-alcoholic steatohepatitis (NASH) are becoming the most significant causes of liver disease worldwide, without any approved drugs for their treatment. The risk of NASH and advanced fibrosis is higher in postmenopausal females than males independently of metabolic factors (Bambha et al, 2012). The pathophysiology of NASH and NAFLD displays sex-linked differences, explaining that liver-targeted drugs may target distinct mechanisms in men and women. This might be the case in a randomized phase II clinical trial evaluating the therapeutic effect of cenicriviroc (a dual C-C chemokine receptor 2 and 5 antagonist) against NASH with fibrosis. The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; NASH is considered an independent risk factor of cardiovascular diseases. NASH displays sexlinked epidemiological, phenotypical, and molecular differences; little is known about the background of these sex-specific differences on the molecular level
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