Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Abstract

Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

“…PPAR-␣ agonists were recently shown to stimulate Mdr2 overexpression, 44 suggesting that this finding could rather be related to the PPAR-␣-activating capacity of atorvastatin. 22 Because an imbalance in the biliary phospholipid and bile acid ratio in Mdr2 knockout mice leads to a cholestatic phenotype resembling primary sclerosing cholangitis, 15,17 it is attractive to speculate that induction of Mdr2 and biliary phospholipid secretion by statins might protect bile ducts against toxic bile acids. [11][12][13] In addition, Asbt was only induced by atorvastatin, which-analogous to human ASBT-could be related to PPAR-␣ stimulation.…”

“…4B). Because statins were reported to activate peroxisome proliferator-activated receptor ␣ (PPAR-␣), 22 we also determined mRNA levels of the classical PPAR-␣ target gene acyl-coenzyme A oxidase-1. Only atorvastatin was able to significantly induce acyl-coenzyme A oxidase-1 (1.9-fold), while treatment with PB, TCPOBOP, and PCN did not show any induction (data not shown).…”

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

“…31,42 Moreover, statins have been shown to stimulate biliary excretion of phospholipids 34,35 that may further protect bile ducts from immunomediated injury in PBC. 43,44 This may be explained by activation of the nuclear peroxisome proliferator-activated receptor-␣, 45 which is predicted to modulate biliary bile acid/phospholipid ratio via increased biliary phospholipid secretion and increased cholangiocellular reabsorption of biliary bile acids, 31,46 resulting in less aggressive bile.…”

PPARα mediates the anti‐inflammatory effect of simvastatin in an experimental model of zymosan‐induced multiple organ failure

“…In addition to their effect on plasma lipid concentrations, statins exert such pleiotropic activities as anti-platelet, anti-oxidant, anti-inflammatory and immunomodulatory activity (Fehrana et al, 2009;Liu et al, 2009). Cross-talk between statins and PPARa was first demonstrated by Martin et al (2001) in human HepG2 hepatoma cells, and subsequent studies showed that statins increase PPARa mRNA levels (Landrier et al, 2004;Sanguino et al, 2005).…”