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Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease
Olufunto O Badmus1, Zachary A Kipp2, Evelyn A Bates2
1Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States.
Insights
Loss of hepatic PPARα in mice leads to nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) by increasing liver fat and vascular stiffness. Hepatic PPARα protects the cardiovascular system from NAFLD-induced damage.
Area of Science:
- Hepatology
- Cardiovascular Science
- Metabolic Disease Research
Background:
- Cardiovascular disease (CVD) is the primary cause of mortality in nonalcoholic fatty liver disease (NAFLD) patients, but underlying mechanisms remain unclear.
- Hepatocyte-specific deletion of proliferator-activated receptor-α (PPARα) in mice (PparaHepKO) results in hepatic steatosis, mimicking NAFLD.
- This study investigates if PparaHepKO mice exhibit exacerbated cardiovascular phenotypes due to increased liver fat.
Purpose of the Study:
- To determine the impact of hepatic PPARα deficiency on cardiovascular health in a mouse model of NAFLD.
- To elucidate the mechanisms by which hepatic PPARα influences cardiovascular parameters.
- To explore the role of hepatic PPARα in protecting against NAFLD-associated CVD.
Main Methods:
- Utilized PparaHepKO and control littermate mice on a standard chow diet for 30 weeks.
- Assessed hepatic fat content using Echo MRI, hepatic triglycerides, and Oil Red O staining.
- Evaluated cardiovascular parameters including mean arterial blood pressure, diastolic function, cardiac remodeling, and aortic stiffness.
- Measured kinase activity in aortic tissue using PamGene technology.
Main Results:
- PparaHepKO mice showed significantly increased hepatic fat content and triglycerides compared to controls, without differences in body weight or glucose/insulin levels.
- These mice exhibited elevated mean arterial blood pressure, impaired diastolic function, cardiac remodeling, and increased aortic stiffness.
- Loss of hepatic PPARα was associated with reduced kinase activity of tropomyosin receptor kinases and p70S6K in the aorta.
Conclusions:
- Hepatic PPARα deficiency promotes NAFLD and associated cardiovascular complications, including hypertension and vascular dysfunction.
- Alterations in aortic kinase activity following hepatic PPARα loss may contribute to the pathogenesis of NAFLD-induced CVD.
- Hepatic PPARα plays a protective role in the cardiovascular system, potentially through mechanisms yet to be fully defined.
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-α (PPARα) (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 PPARα 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 PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.
