Loss of hepatic PPAR alpha in mice causes hypertension and cardiovascular disease

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-alpha (PPAR alpha) (Ppara(HepKO)) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the Ppara(HepKO) mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used Ppara(HepKO) 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 Ppara(HepKO) 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 Ppara(HepKO) 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 PPAR alpha 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 PPAR alpha protects the cardiovascular system through some as-of-yet undefined mechanism.

Automated summary

Cardiovascular disease (CVD) is the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). A study using mice deficient in hepatic proliferator-activated receptor-alpha (PPAR alpha) found that the lack of PPAR alpha led to increased liver fat content and higher risk of NAFLD, as well as impaired cardiovascular function and enhanced vascular stiffness.