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

Németh, Krisztina and Tóth, Blanka and Sarnyai, Farkas and Koncz, Anna and Lenzinger, Dorina and Kereszturi, Éva and Visnovitz, Tamás and Kestecher, Brachyahu Meir and Osteikoetxea, Xabier and Csala, Miklós and Buzás, Edit I. and Tamási, Viola (2023) High fat diet and PCSK9 knockout modulates lipid profile of the liver and changes the expression of lipid homeostasis related genes. NUTRITION & METABOLISM, 20 (1). No.-19. ISSN 1743-7075

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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 verif ied 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.

Item Type: Article
Additional Information: Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad Tér 4, Budapest, 1085, Hungary ELKH-SE Translational Extracellular Vesicle Research Group, Nagyvárad Tér 4, Budapest, 1085, Hungary Department of Molecular Biology, Semmelweis University, Tűzoltó U. 37-47, Budapest, 1094, Hungary Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Műegyetem Rkp. 3, Budapest, 1111, Hungary Department of Plant Physiology and Molecular Plant Biology, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, 1117, Hungary HCEMM-SE Extracellular Vesicle Research Group, Nagyvárad Tér 4, Budapest, 1085, Hungary Export Date: 5 May 2023 Correspondence Address: Tamási, V.; Department of Molecular Biology, Tűzoltó U. 37-47, Hungary; email:
Uncontrolled Keywords: Liver, Dyslipidemia, Hepatosteatosis, PCSK9, LDLR, CD36, ANXA2
Subjects: R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat
R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan > RM215-RM216 Nutrition, Dietetics / Táplálkozás, dietetika
Depositing User: MTMT SWORD
Date Deposited: 04 Apr 2024 09:53
Last Modified: 04 Apr 2024 09:53

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