Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin–Angiotensin System

Abstract

Objective-Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular reninangiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results-We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II-mediated mitogenactivated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes. Conclusions-Two

Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

“…2A, red bars) show decreased ability to stimulate adipocyte differentiation to varying degrees. Consistent with prior work, variants reported to segregate with disease in FPLD3 families show the most severe LOF with those that reside in the DNA binding domain (p.R165T, p.C159Y, and p.Y151C), almost completely inactivating PPARG (9)(10)(11).…”

Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

“…In contrast, patients with dominant negative (DN) mutations in PPAR-␥ (V290M or P467L) (4) exhibit severe early onset hypertension and insulin resistance. Other mutations in human PPAR-␥ (R165T or L339X) cause hypertension and lipodystrophies (3). Taken together, these observations indicate a significant requirement for functional PPAR-␥ in the regulation of cardiovascular homeostasis.…”

Primary Intestinal Follicular Lymphoma and Premature Atherosclerosis in a Japanese Diabetic Patient with Atypical Familial Partial Lipodystrophy

“…The level of adiponectin may also have had an effect on atherosclerosis in the present case. Therefore, because our patient was a woman with FPL and exhibited clustering of atherogenic risk factors, such as diabetes mellitus, hypertriglyceridemia and a low serum levels of adiponectin, it is conceivable that atherogenic risk factors and other factors, including unidentified causative genes affect the development of atherosclerosis, as we previously reported (30)(31)(32)(33)(34)(35).…”