Propionate Promotes Fatty Acid Oxidation through the Up-Regulation of Peroxisome Proliferator-Activated Receptor &alpha; in Intestinal Epithelial Cells

Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator–activated receptor α (PPARα) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPARα and the FAO pathway–associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPARα protein expression associated with increased expression of PPARα-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPARα expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF-β–induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPARα−/− mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPARα signaling during aging aggravates renal fibrosis development, and targeting PPARα is useful for preventing age-associated CKD.

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Activation of Peroxisome Proliferator-Activated Receptor (PPAR) Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

Diabetes ◽

10.2337/db07-1318 ◽

2007 ◽

Vol 57 (2) ◽

pp. 332-339 ◽

Cited By ~ 231

Author(s):

U. Riserus ◽

D. Sprecher ◽

T. Johnson ◽

E. Olson ◽

S. Hirschberg ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Metabolic Abnormalities ◽

Peroxisome Proliferator Activated Receptor

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Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor α Transcriptional Up-Regulation of Fatty Acid Oxidation

Endocrinology ◽

10.1210/en.2004-0667 ◽

2005 ◽

Vol 146 (1) ◽

pp. 375-382 ◽

Cited By ~ 71

Author(s):

Sandrine Gremlich ◽

Christopher Nolan ◽

Raphaël Roduit ◽

Rémy Burcelin ◽

Marie-Line Peyot ◽

...

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Pancreatic Islet ◽

Cellular Response ◽

Uncoupling Protein ◽

Acid Oxidation ◽

Hyperinsulinemic Hypoglycemia ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-α (PPARα)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARα null (PPARαKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARα expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARα expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARαKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARα null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARα, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARα, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

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PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00457.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. H239-H249 ◽

Cited By ~ 19

Author(s):

Stephen W. Standage ◽

Brock G. Bennion ◽

Taft O. Knowles ◽

Dolena R. Ledee ◽

Michael A. Portman ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Mouse Models ◽

Heart Function ◽

Left Ventricular ◽

Cardiac Response ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Regulatory State ◽

Peroxisome Proliferator Activated Receptor

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα ( Ppara−/−) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara−/− mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara−/− mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara−/− mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.

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