PhD Scientific Days 2026

Poster Session 3.U - Molecular Medicine

The role of PCSK9 in insulin receptor regulation and diet-induced insulin resistance

Name of the presenter

Palczert, Zoltán

Institute/workplace of the presenter

Department of Molecular Biology, Semmelweis University

Authors

Zoltán Palczert¹, Csongor Máté Habány¹, Anja Baumann², Ina Bergheim², Miklós Csala¹, Viola Tamási¹
1: Department of Molecular Biology, Semmelweis University, Budapest, Hungary
2: University of Vienna, Department für Ernährungswissenschaften, Vienna, Austria

Text of the abstract

Introduction:
The prevalence of type 2 diabetes mellitus is increasing worldwide. One of the major risk factors for this disease is obesity. Elevated lipid levels contribute to insulin resistance and pancreatic damage, which disrupt blood glucose regulation and further disturb lipid metabolism, altogether leading to a combined condition known as diabetic dyslipidemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the most important regulators of cellular cholesterol uptake, as it increases LDLR internalization in both the liver and the pancreas. It also regulates the internalization of other membrane receptors, such as CD36 and APOER2.
Aims:
Our goal is to test the hypothesis that, in addition to regulating lipid homeostasis, PCSK9 has a significant effect on the development of insulin resistance through regulating the internalization of insulin receptor (IR). We also aim to analyze the effect of various lipids on the IR–PCSK9 interaction in HepG2 cells to reveal potential health effects of these components. The relationship between diet, insulin resistance, and PCSK9 levels is also investigated in mice in vivo.
Methods:
qPCR was used to assess PCSK9 and INSR mRNA expression, while ELISA was applied to measure PCSK9 protein levels. Flow cytometry was used to determine membrane expression and internalization of the insulin receptor. To gain deeper insight into the intracellular regulation of PCSK9, siRNA knockdown experiments were performed.
Results:
As expected, we observed diet-dependent changes in IR and PCSK9 levels in mice. Different lipid components of the diet had distinct effects on PCSK9 levels. Depletion of PCSK9 with evolocumab increased the expression of IR and decreased the rate of its endocytosis. These findings suggest that IR internalization may indeed be regulated by PCSK9.
Conclusion:
Our results demonstrate that different lipids have a strong impact on PCSK9 mRNA expression. We also conclude that PCSK9 plays a significant role in the regulation of IR at multiple levels. Collectively, our findings suggest that PCSK9 is a potential target for dietary and/or pharmacological interventions aimed at modulating insulin resistance.
Funding:
TKP2021-EGA-24 was implemented with support from Hungary’s Ministry of Innovation and Technology through the National Research, Development and Innovation Fund under the TKP2021-EGA scheme.