Author:
Németh Krisztina,Tóth Blanka,Sarnyai Farkas,Koncz Anna,Lenzinger Dorina,Kereszturi Éva,Visnovitz Tamás,Kestecher Brachyahu Meir,Osteikoetxea Xabier,Csala Miklós,Buzás Edit I.,Tamási Viola
Abstract
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Funder
National Cardiovascular Laboratory Program
Hungarian National Research, Development and Innovation Office
Higher Education Excellence Program (FIKP), Therapeutic Thematic Programme
Horizon 2020
ELKH SE Translational Extracellular Vesicle Research Group
INKUBÁTOR program of the Department of Molecular Biology, Semmelweis University, Budapest
Semmelweis University
Publisher
Springer Science and Business Media LLC
Subject
Nutrition and Dietetics,Endocrinology, Diabetes and Metabolism,Medicine (miscellaneous)
Reference59 articles.
1. Csonka C, Baranyai T, Tiszlavicz L, et al. Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas. Lipids Health Dis. 2017. https://doi.org/10.1186/s12944-017-0537-z.
2. Weber LW, Boll M, Stampfl A. Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins. World J Gastroenterol. 2004. https://doi.org/10.3748/wjg.v10.i21.3081.
3. Pirillo A, Casula M, Olmastroni E, Norata GD, Catapano AL. Global epidemiology of dyslipidaemias. Nat Rev Cardiol. 2021. https://doi.org/10.1038/s41569-021-00541-4.
4. World Health Organization. Mortality and global health estimates. The top 10 causes of death. 2019. Available in: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
5. Begg MJ, Sturrock ED, van der Westhuyzen DR. Soluble LDL-R are formed by cell surface cleavage in response to phorbol esters. Eur J Biochem. 2004. https://doi.org/10.1046/j.1432-1033.2003.03953.x.