LAUSR

Peroxisome proliferator-activated receptor α (PPARα) is a member of the steroid/nuclear receptor superfamily and functions as a ligand-activated transcription factor. After ligand binding, PPARα forms a heterodimer with the retinoid X receptor, and the heterodimer binds to DNA sequences, called PPAR response elements. Activated PPARα increases the expression of numerous target genes encoding enzymes involved in fatty acid/triglyceride (TG) transport and metabolism, gluconeogenesis, phospholipid secretion, amino acid metabolism, inflammation, oxidative stress, apoptosis, and autophagy. PPARα negatively modulates a small subset of other genes through an unknown mechanism. PPARα is highly expressed in organs that use fatty acids as a fuel source, particularly under fasting and low glucose conditions, such as liver, heart, kidney, skeletal muscle, and adipose tissue. PPARα has important physiological roles that are associated in some cases with tissue protective functions, including the maintenance of lipid catabolism and energy generation, anti-inflammatory effects, antioxidative stress, and anti-apoptotic effects. PPARα was reported to be activated by various endogenous and synthetic ligands. Notably, long-chain polyunsaturated fatty acids and eicosanoids, such as leukotriene B4, hydroxyeicosatetraenoic acids, and prostaglandins D1 and D2, have exhibited PPARα agonist activities. PPARα is activated by synthetic PPARα agonists with the most important and widely studied being the fibrates, such as Wy-14643, and the clinically used hyperlipidemic drugs gemfibrozil, bezafibrate, clofibrate, and fenofibrate. 3 Fibrates strongly decrease TG and increase high-density lipoprotein (HDL) cholesterol levels in the blood. Therefore, fibrates are used clinically as hypolipidemic and anti-atherosclerotic medicines. The favorable metabolic effects of fibrates have been attributed to PPARα activation.While this remains a subject of investigative interest, the current understanding of the hypolipidemic mechanisms associated with fibrates elucidated so far is as follows. First, fibrates promote lipolysis of plasma TG and cellular consumption of its metabolites. In general, lipoproteins containing TG circulate in the blood, and the plasma TGs are degraded to free fatty acids (FFAs) and glycerol by lipoprotein lipase (LPL) expressed on the vascular endothelium. LPL activity is promoted by apolipoprotein C-II and, conversely, suppressed by apolipoprotein C-III (apoC-III). FFAs derived from lipolysis are trafficked into the cells of systemic organs, including the liver, muscle, kidney, and adipocytes, via cell membrane transporters and intracellular carrier proteins such as fatty acid transport protein (FATP) and fatty acid binding protein (FABP), respectively. They are then degraded by β-oxidation in mitochondria and peroxisomes for use as an energy source. The stimulation of fatty acid oxidation decreases cellular TG synthesis and contributes to lowered secretion of TG-rich very low-density lipoprotein. PPARα activation induces increased mRNA/protein expression and activation of important lipid-metabolizing enzymes, including LPL, FATP, FABP, and β-oxidation enzymes, while negatively modulating apoC-III expression. This results in promotion of lipolysis, FFA consumption, and decreased plasma TG levels. Second, PPARα activation by fibrates is known to upregulate important anti-atherosclerotic high-density lipoprotein (HDL) components, apolipoprotein A-1, and apolipoprotein A-II, resulting in increased HDL. This increase in HDL reverses cholesterol transport and attenuates vascular atherosclerotic lesions. Third, PPARα activation by fibrate was reported to increase LDL receptor-mediated clearance of LDL through inhibiting the expression of apoC-III and PCSK9, which are PPARα target molecules inhibiting LDL receptor-mediated LDL uptake. Fibrates have also reported to form LDL with a high affinity for the LDL receptor rendering LDL more susceptible to catabolism. It is via these various mechanisms fibrates exert their favorable hypolipidemic effects. Because the production and secretion of lipoproteins occur in the liver, hepatic PPARα may be the principle species responsible for these hypolipidemic actions. On the other hand, PPARα and its target molecules, including LPL and β-oxidation enzymes, are expressed in various organs. Therefore, through the promotion of lipolysis, digestion of FFAs, and stimulation of plasma TG clearance, the principal pharmacological actions of fibrates would be expected to occur systemically. For these reasons, the importance of hepatic PPARα in the metabolic effects of fibrates is still unclear. In this issue of the Journal of Gastroenterology and Hepatology, Li, Brocker et al. demonstrate that the hypolipidemic effects of a representative PPARα agonist, Wy-14643, are completely abolished in liver-specific PPARα-deficient mice. This result suggests that the hypolipidemic effects of fibrates are dependent on activation of hepatic PPARα. Hence, among the various organs expressing PPARα, the hepatic form is the most important for the metabolic action of fibrates. The adverse effects of fibrates, such as rhabdomyolysis, were thought to be related to activation of PPARα in extrahepatic tissues, such as skeletal muscle. Thus, a compound that can specifically target and activate hepatic PPARα may become a more desirable hypolipidemic agent with fewer adverse effects than the less specific activators. Because Li, Brocker et al. only explored the hypolipidemic actions caused by short-term administration of fibrate over 2 days, it is possible that long-term administration may lead to systemic PPARα activation and off-target effects other than lipid lowering. However, there is no doubt that hepatic PPARα is the most sole factor responsible for the immediate lipid-lowering effects of fibrates. To investigate whether PPARα activation in other organs would influence the lipid effects of fibrates, a study using mice deficient in each organ-specific PPARα will be necessary. Moreover, the study by Li, Brocker et al. demonstrate a very interesting phenomenon that hepatic PPARα might strongly influence feeding behavior. It has been previously reported that fibrate treatment suppressed food intake. The mechanism of hypophagia by PPARα agonists is reportedly related to effects doi:10.1111/jgh.14126