High fat diet and PCSK9 knockout modulates lipid profile of the liver and changes the expression of lipid homeostasis related genes

CD36 PCSK9 内分泌学 内科学 低密度脂蛋白受体 血脂异常 甘油三酯 脂多糖学 脂肪肝 血脂谱 脂质代谢 生物 肝X受体 胆固醇 受体 脂蛋白 医学 糖尿病 生物化学 核受体 基因 转录因子 疾病
作者
Krisztína Németh,Blanka Tóth,Farkas Sarnyai,Anna Koncz,Dorina Lenzinger,Éva Kereszturi,Tamás Visnovitz,Brachyahu M. Kestecher,Xabier Osteikoetxea,Miklós Csala,Edit I. Buzás,Viola Tamási
出处
期刊:Nutrition & Metabolism [BioMed Central]
卷期号:20 (1) 被引量:11
标识
DOI:10.1186/s12986-023-00738-z
摘要

High fat diet (HFD) increases the likelihood of dyslipidemia, which can be a serious risk factor for atherosclerosis, diabetes or hepatosteatosis. Although changes in different blood lipid levels were broadly investigated, such alterations in the liver tissue have not been studied before. The aim of the current study was to investigate the effect of HFD on hepatic triglyceride (TG), diglyceride (DG) and ceramide (CER) levels and on the expression of four key genes involved in lipid homeostasis (Pcsk9, Ldlr, Cd36 and Anxa2) in the liver. In addition, the potential role of PCSK9 in the observed changes was further investigated by using PCSK9 deficient mice.We used two in vivo models: mice kept on HFD for 20 weeks and PCSK9-/- mice. The amount of the major TGs, DGs and CERs was measured by using HPLC-MS/MS analysis. The expression profiles of four lipid related genes, namely Pcsk9, Ldlr, Cd36 and Anxa2 were assessed. Co-localization studies were performed by confocal microscopy.In HFD mice, hepatic PCSK9 expression was decreased and ANXA2 expression was increased both on mRNA and protein levels, and the amount of LDLR and CD36 receptor proteins was increased. While LDLR protein level was also elevated in the livers of PCSK9-/- mice, there was no significant change in the expression of ANXA2 and CD36 in these animals. HFD induced a significant elevation in the hepatic levels of all measured TG and DG but not of CER types, and increased the proportion of monounsaturated vs. saturated TGs and DGs. Similar changes were detected in the hepatic lipid profiles of HFD and PCSK9-/- mice. Co-localization of PCSK9 with LDLR, CD36 and ANXA2 was verified in HepG2 cells.Our results show that obesogenic HFD downregulates PCSK9 expression in the liver and causes alterations in the hepatic lipid accumulation, which resemble those observed in PCSK9 deficiency. These findings suggest that PCSK9-mediated modulation of LDLR and CD36 expression might contribute to the HFD-induced changes in lipid homeostasis.
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