Loss of hepatic PPARa in mice causes hypertension and cardiovascular disease

Olufunto O. Badmus, Zachary A. Kipp, Evelyn A. Bates, Alexandre A. da Silva, Lucy C. Taylor, Genesee J. Martinez, Wang Hsin Lee, Justin F. Creeden, Terry D. Hinds, David E. Stec

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte proliferator-activated receptor-a (PPARa) (PparaHepKO) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 wk on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared with littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, P < 0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01 mM, P < 0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, P < 0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity in this tissue. Our data suggest that the loss of hepatic PPARa induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARa protects the cardiovascular system through some as-of-yet undefined mechanism.

Original languageEnglish
Pages (from-to)R81-R95
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume325
Issue number1
DOIs
StatePublished - Jul 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 the American Physiological Society.

Keywords

  • cardiac dysfunction
  • hepatic steatosis
  • hypertension
  • lean NAFLD
  • nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • General Medicine

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