Molecular Actions of PPARα in Lipid Metabolism and Inflammation

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.

Exercise and Dairy Protein have Distinct Effects on Indices of Liver and Systemic Lipid Metabolism

“…Acc1 mRNA expression was also reduced by exercise (Figure F), with concomitant reductions in ACC1 protein content (Figure G). Exercise, but not SMP, increased the mRNA expression of Ppara , a transcription factor that regulates genes involved in fatty acid oxidation (Figure G). Supporting this, two genes regulated by PPARα, namely carnitine palmitoyltransferase 1 alpha, liver ( Cpt1a ) and β‐Had ( P = 0.09), were also increased by exercise.…”

Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

“…">PPARα and Hepatic Lipid CatabolismPPARα controls the expression of several genes involved in a plethora of lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial β-oxidation, FA binding and activation, FA elongation and desaturation, synthesis and lipolysis, lipoprotein metabolism, gluconeogenesis, and bile acid metabolism [3]. Consistent with its action, PPARα is widely expressed in tissues with high FA oxidation rates, such as heart, liver, and skeletal muscle, and serves as a major regulator of FA homeostasis [10,11]. The human and mouse PPARα genes which share 91% homology are located on chromosome 22 and chromosome 15, respectively [10].PPARα ligands are FA derivatives formed during lipolysis, lipogenesis, or FA catabolism.…”

“…Consistent with its action, PPARα is widely expressed in tissues with high FA oxidation rates, such as heart, liver, and skeletal muscle, and serves as a major regulator of FA homeostasis [10,11]. The human and mouse PPARα genes which share 91% homology are located on chromosome 22 and chromosome 15, respectively [10].PPARα ligands are FA derivatives formed during lipolysis, lipogenesis, or FA catabolism. Animal studies involving genetic disruption of the first rate-limiting peroxisomal β-oxidation enzyme, acyl-CoA oxidase 1 (ACOX1), suggest that its substrates likely are PPARα agonists [12].…”

“…However, upon ligand binding nuclear corepressors are released and replaced by coactivators such as PGC1α which, via histone acetylase (HAT) activity, derepress and induce the expression of PPARα target genes involved in hepatic lipid and glucose metabolism. The wide repertoire of genes that is induced in liver after PPARα activation, is suggestive of its central regulatory role in hepatic lipid metabolism [10,16]. These genes include FA transporter, FAT/CD36 and fatty acid-binding protein (L-FABP), and rate-limiting enzymes of peroxisomal β-oxidation, including acyl-CoA oxidase 1 (ACOX1) and L-bifunctional enzyme (EHHADH), most pronouncedly in rodents.…”

“…These genes include FA transporter, FAT/CD36 and fatty acid-binding protein (L-FABP), and rate-limiting enzymes of peroxisomal β-oxidation, including acyl-CoA oxidase 1 (ACOX1) and L-bifunctional enzyme (EHHADH), most pronouncedly in rodents. Additionally, both rodent and primate carnitine palmitoyltransferase I and II (CPT-I and CPT-II) protein, localized in the outer and inner mitochondrial membrane, respectively, are regulated by PPARα [10,16]. Moreover, PPARα regulates the critical reaction of mitochondrial β-oxidation by directly controlling medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD), very long-chain acyl-CoA dehydrogenase (VLCAD), and mitochondrial 3-hydroxy3-methylglutaryl-CoA synthase (mHMGCoAS) expression levels [10,16].…”