Dennd5b-Deficient Mice are Resistant to PCSK9-Induced Hypercholesterolemia and Diet-Induced Hepatic Steatosis

Maura Mobilia, Callie Whitus, Alexander Karakashian, Hong S. Lu, Alan Daugherty, Scott M. Gordon

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1 Scopus citations

Abstract

Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b/ mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b+/ + mice, Dennd5b/ mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b/ compared to Dennd5b+/+ mice. Additionally, Dennd5b/ mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b+/+ mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b/ liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.

Original languageEnglish
Article number100296
JournalJournal of Lipid Research
Volume63
Issue number12
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute K22HL141299 (S. M. G); National Institute of Digestive, Diabetes and Kidney Diseases R01DK133184 (S. M. G); the National Institute of General Medical Sciences P30GM127211 (Pilot award to S. M. G); and by institutional funds from the University of Kentucky (S. M. G). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.

Keywords

  • atherosclerosis
  • cholesterol
  • dietary fat
  • hepatic steatosis
  • lipids
  • lipoproteins
  • liver
  • proprotein convertase subtilisin/kexin type 9 serine protease
  • triglyceride

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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