The loss of hepatic PPARα prompts fatty liver disease-induced hypertension and cardiovascular disease

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Authors: Badmus, Olufunto, Kipp, Zachary Kipp, Bates, Evelyn, da Silva, Alexandre, Taylor, Lucy, Martinez, Genesee, Hinds, Terry, Stec, David
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5723348

Abstract only Non-alcoholic fatty liver disease (NAFLD) often clusters with obesity, diabetes, and hyperlipidemia. For unknown reasons, the leading cause of death in patients with NAFLD is cardiovascular disease (CVD). Most preclinical models of NAFLD are induced by high-fat diet feeding that induces obesity and glucose intolerance, each provoking CVD independent of changes in hepatic fat. To determine the role of NAFLD in the promotion of CVD, independent of changes in body weight and insulin sensitivity, we utilized our hepatocyte-specific PPARα knockout ( Ppara HepKO ) and littermate control ( Ppara fl / fl ) mice. After 30 weeks on a standard diet, male Ppara HepKO mice exhibited elevated hepatic fat content compared to 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 ± 0.01mM, p<0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The Ppara HepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, p<0.05), impaired diastolic function, and adverse cardiac remodeling consisting of dilated cardiomyopathy. The mice with the loss of hepatic PPARα displayed alterations in vascular stiffness, including increased pulsatility index, resistive index, and intima-media thickness in the abdominal aorta and carotid artery, which was corroborated with reduced kinase signaling in the aortas of the Ppara HepKO mice. Our findings indicate that hepatic PPARα is vital in protecting the cardiovascular system via a liver-specific mechanism. Also, the  Ppara HepKO mice are possibly a novel model for studying NAFLD-induced CVD. This work was supported by National Institute of Health R01DK126884, and the National Heart, Lung and Blood Institute P01 HL05197-11 (D.E.S) and the National Institute of General Medical Sciences P20GM104357-02. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.