Eicosapentaenoic acid (EPA) in fish oil is known to improve hepatic steatosis. However, it remains unclear whether such action of EPA is actually caused by peroxisome proliferator-activated receptor α (PPARα) activation. To explore the contribution of PPARα to the effects of EPA itself, male wild-type and Ppara-null mice were fed a saturated fat diet for 16 weeks, and highly (>98%)-purified EPA was administered in the last 12 weeks. Furthermore, the changes caused by EPA treatment were compared to those elicited by fenofibrate (FF), a typical PPARα activator. A saturated fat diet caused macrovesicular steatosis in both genotypes. However, EPA ameliorated steatosis only in wild-type mice without PPARα activation, which was evidently different from numerous previous observations. Instead, EPA inhibited maturation of sterol-responsive element-binding protein (SREBP)-1 in the presence of PPARα through down-regulation of SREBP cleavage-activating protein and site-1 protease. Additionally, EPA suppressed fatty acid uptake and promoted hydrolysis of intrahepatic triglycerides in a PPARα-independent manner. These effects were distinct from those of fenofibrate. Although fenofibrate induced NAPDH oxidase and acyl-coenzyme A oxidase and significantly increased hepatic lipid peroxides, EPA caused PPARα-dependent induction of superoxide dismutases, probably contributing to a decrease in the lipid peroxides. These results firstly demonstrate detailed mechanisms of steatosis-ameliorating effects of EPA without PPARα activation and ensuing augmentation of hepatic oxidative stress.

The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) ␣ activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (Ն50 versus Յ10 mg/kg/day), and thus it remains unclear whether such data can be translated to humans. Furthermore, because bezafibrate is a pan-PPAR activator, the actual contribution of PPAR␣ to its triglyceride-lowering properties remains undetermined. To address these issues, bezafibrate at clinically relevant doses (10 mg/kg/day; low) was administered to wild-type and Ppara-null mice, and its effects were compared with those from conventionally used doses (100 mg/kg/day; high). Pharmacokinetic analyses showed that maximum plasma concentration and area under the concentration-time curve in bezafibrate-treated mice were similar to those in humans at low doses, but not at high doses. Low-dose bezafibrate decreased serum/liver triglycerides in a PPAR␣-independent manner by attenuation of hepatic lipogenesis and triglyceride secretion. It is noteworthy that instead of PPAR activation, down-regulation of sterol regulatory element-binding protein (SREBP)-1c was observed in mice undergoing low-dose treatment. High-dose bezafibrate decreased serum/liver triglycerides by enhancement of hepatic fatty acid uptake and ␤-oxidation via PPAR␣ activation, as expected. In conclusion, clinically relevant doses of bezafibrate exert a triglyceride-lowering effect by suppression of the SREBP-1c-regulated pathway in mice and not by PPAR␣ activation. Our results may provide novel information about the pharmacological mechanism of bezafibrate action and new insights into the treatment of disorders involving SREBP-1c.Bezafibrate and other fibrate drugs are clinically used as hypolipidemic agents to preferentially lower serum triglyceride (TG) levels. Several large-scale clinical trials have demonstrated a relationship between the TG-lowering effect of fibrates and a reduction in the risk of cardiovascular events in patients with dyslipidemia, type 2 diabetes mellitus, and metabolic syndrome (BIP Study Group, 2000;Keech et al., 2005;Tenenbaum et al., 2005). The mechanisms accounting for the hypolipidemic effect of fibrates in humans are explained mainly as an increase in the lipolysis of TG-rich lipoproteins, such as very-low-density lipoprotein (VLDL),

Epidemiological studies demonstrate a possible relationship between chronic ethanol drinking and thrombotic diseases, such as myocardial infarction and stroke. However, the precise mechanism for this association remains unclear. Sulfatides are endogenous glycosphin-golipids composed of ceramide, galactose, and sulfate, known to have anti-thrombotic properties. Low (0.5 g/kg/ day), middle (1.5 g/kg/day), and high (3.0 g/kg/day) doses of ethanol were administered for 21 days intraperitoneally to female wild-type mice, and serum/liver sulfatide levels were measured. No significant changes in cholesterol and triglycerides were seen in serum and liver by ethanol treatment. However, serum/liver sulfatide levels were significantly decreased by middle- and high-dose ethanol treatment, likely due to downregulation of hepatic cerebro-side sulfotransferase (CST) levels. Marked decreases in the expression of catalase and superoxide dismutases and ensuing increases in lipid peroxides were also observed in the livers of mice with middle- and high-dose ethanol treatment, suggesting the association between the suppression of hepatic CST expression and enhancement of oxidative stress. Furthermore, serum levels of tissue factor, a typical pro-coagulant molecule, were significantly increased in the mice with middle- and high-dose ethanol treatment showing decreases in serum sulfatide levels. Collectively, these results demonstrate that chronic ethanol consumption reduces serum sulfatide levels by increasing oxidative stress and decreasing the expression of CST in the liver. These findings could provide a mechanism by which chronic ethanol drinking increases thrombotic events.

After a single oral dose of silodosin in male rats ， male dogs and healthy human male volunteers ， Cmax occurred with − in about 2 h ， indicating rapid absorption ． The elimination half − 1ife was about 2 h in rat and dog， but 4． 7 h (fasted)and 6． Oh (non − fasted)in humans ． Absolute bioavailability values in rat ， dog and human were about 9 ， 25 and 32 ％ ， respec − tive 且 y ， In rat and dog ， total blood clearance was almost equivalent to the hepatic blood flow ， but that in human was low (20 ％)， demonstrating a large species difference in hepatic clearance ． ln each species ， the apparent volume of distribu − tion exceeded the vo 【 ume of total body water ． After an oral dose of i4C ・ silodosin to male rats ， radioactivity was rapidly and widely distributed to most tissues ． The highest concentrations outside the gastrointestinal tract were found in liver and kidney， with only 且 ow concentrations in brain tissues ． The in vitro plasma protein binding of silodosin was about 80 ％ in rat and dog， and 95， 6％ in humans ， with α 1 − acid glycoprotein(AGP)contributing to the binding profile ． Silodosin was found to be a dual substrate for CYP3A4 and ρ 一 glycoprotein ． In human plasma ， two major metabolites generated by UDP − glucuronosyltransferase (UGT ；UGT2B7)and alcohol ／ aldehyde dehydrogenase (ADH ／ ALDH) were found ， but no glucuronide conjugates were detected in rat or dog plasma ． After a single oral dose of 且 4C − silodosin in rat ， dog and human ， the urinary excretion of radioactivity was 15 − 34 ％ ， with that of unchanged silodosin being less than 4 ％ ． The radioactivity was predominantly excreted via the feces ． Key werds − silodosin (KMD − 3213) ；orlA − adrenoceptor antagonist ；pharmacokinetics ；metabolism ；species differences