脂肪性肝炎
脂肪变性
血脂异常
PCSK9
内科学
纤维化
内分泌学
胆固醇
炎症
医学
生物
人口
脂肪肝
生理学
低密度脂蛋白受体
脂蛋白
糖尿病
疾病
环境卫生
作者
Dániel Kucsera,Viktória Tóth,Dorottya Gergő,Imre Vörös,Zsófia Onódi,Anikó Görbe,Péter Ferdinándy,Zoltán V. Varga
标识
DOI:10.3389/fphys.2021.609465
摘要
Background The 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. Objectives We 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 Results We 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. Conclusion This 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.
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