Liraglutide downregulates hepatic LDL receptor and PCSK9 expression in HepG2 cells and db/db mice through a HNF-1a dependent mechanism.

ABSTRACT: BACKGROUND:Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9. METHODS:At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1?) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 ?g/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt. RESULTS:Firstly, liraglutide suppressed both PCSK9 and HNF1? expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1? in db/db mice but not in WT mice. CONCLUSIONS:Liraglutide suppressed PCSK9 expression through HNF1?-dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice.

SUBMITTER: Yang SH 

PROVIDER: S-EPMC5885408 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature