Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets

Peroxisome proliferator-activated receptor (PPAR) alpha is a transcription factor controlling lipid and glucose homeostasis. PPAR alpha-deficient (-/-) mice are protected from high-fat diet-induced insulin resistance. However, the impact of PPAR alpha in the pathophysiological setting of obesity-related insulin resistance is unknown. Therefore, PPAR alpha(-/-) mice in an obese (ob/ob) background were generated. PPAR alpha deficiency did not influence the growth curves of the obese mice but surprisingly resulted in a severe, age-dependent hyperglycemia. PPAR alpha deficiency did not aggravate peripheral insulin resistance. By contrast, PPAR alpha(-/-) ob/ob mice developed pancreatic beta-cell dysfunction characterized by reduced mean islet area and decreased insulin secretion in response to glucose in vitro and in vivo. In primary human pancreatic islets, PPAR alpha agonist treatment prevented fatty acid-induced impairment of glucose-stimulated insulin secretion, apoptosis, and triglyceride accumulation. These results indicate that PPAR alpha improves the adaptative response of the pancreatic beta-cell to pathological conditions. PPAR alpha could thus represent a promising target in the prevention of type 2 diabetes

The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia

Objective - The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. Methods and Results - Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. Conclusion - These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux

Bone Marrow p16(INK4a)-Deficiency Does Not Modulate Obesity, Glucose Homeostasis or Atherosclerosis Development

OBJECTIVE: A genomic region near the CDKN2A locus, encoding p16(INK4a), has been associated to type 2 diabetes and atherosclerotic vascular disease, conditions in which inflammation plays an important role. Recently, we found that deficiency of p16(INK4a) results in decreased inflammatory signaling in murine macrophages and that p16(INK4a) influences the phenotype of human adipose tissue macrophages. Therefore, we investigated the influence of immune cell p16(INK4a) on glucose tolerance and atherosclerosis in mice. METHODS AND RESULTS: Bone marrow p16(INK4a)-deficiency in C57Bl6 mice did not influence high fat diet-induced obesity nor plasma glucose and lipid levels. Glucose tolerance tests showed no alterations in high fat diet-induced glucose intolerance. While bone marrow p16(INK4a)-deficiency did not affect the gene expression profile of adipose tissue, hepatic expression of the alternative markers Chi3l3, Mgl2 and IL10 was increased and the induction of pro-inflammatory Nos2 was restrained on the high fat diet. Bone marrow p16(INK4a)-deficiency in low density lipoprotein receptor-deficient mice did not affect western diet-induced atherosclerotic plaque size or morphology. In line, plasma lipid levels remained unaffected and p16(INK4a)-deficient macrophages displayed equal cholesterol uptake and efflux compared to wild type macrophages. CONCLUSION: Bone marrow p16(INK4a)-deficiency does not affect plasma lipids, obesity, glucose tolerance or atherosclerosis in mice

The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPAR\u3b1

Abstract: Background and aims: Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) is a key regulator of hepatic lipid metabolism and therefore a promising therapeutic target against Metabolic-dysfunction Associated Steatotic Liver Diseases (MASLD). However, its expression and activity decrease during disease progression and several of its agonists did not achieve sufficient efficiency in clinical trials with, surprisingly, a lack of steatosis improvement. Here, we identified the Human leukocyte antigen-F Adjacent Transcript 10 (FAT10) as an inhibitor of PPAR alpha lipid metabolic activity during MASLD progression.Approach and results: In vivo, the expression of FAT10 is upregulated in human and murine MASLD livers upon disease progression and correlates negatively with PPAR alpha expression. The increase of FAT10 occurs in hepatocytes in which both proteins interact. FAT10 silencing in vitro in hepatocytes increases PPAR alpha target gene expression, promotes fatty acid oxidation and decreases intra-cellular lipid droplet content. In line, FAT10 overexpression in hepatocytes in vivo inhibits the lipid regulatory activity of PPAR alpha in response to fasting and agonist treatment in conditions of physiological and pathological hepatic lipid overload.Conclusions: FAT10 is induced during MASLD development and interacts with PPAR alpha resulting in a decreased lipid metabolic response of PPAR alpha to fasting or agonist treatment. Inhibition of the FAT10-PPAR alpha interaction may provide a means to design potential therapeutic strategies against MASLD