Studies on molecular mechanisms of PPARalpha-independent triglyceride-lowering effects of fibrate drugs

本研究检测了临床相关低剂量贝特类药物对饮食诱导的脂肪肝小鼠肝脏脂质代谢的影响。低剂量贝特类药物通过增强肝线粒体脂肪酸β-氧化功能来减少脂肪变性，这不是由于已知的PPARalpha激活。这种新的药理作用似乎与β-氧化酶的蛋白质稳定性增加有关，这可能是由于心磷脂含量增加所致，心磷脂是一种对线粒体蛋白的稳定性/功能性很重要的线粒体特异性磷脂。这些影响不伴随非生理现象，如肝肿大。因此，这些发现可能有助于更好地了解贝特类药物在人类中的作用。

This study examined the effects of clinically relevant low doses of fibrate drugs on hepatic lipid metabolism in mice having diet-induced hepatosteatosis. Low-dose fibrates reduced steatosis through an enhancement of hepatic mitochondrial fatty acid beta-oxidation function, which was not due to known PPARalpha activation. This novel pharmacologic action seemed to be associated with increased protein stability of beta-oxidation enzymes, and this was possibly due to increased contents of cardiolipin, a mitochondria-specific phospholipid important in stability/functionality of mitochondrial proteins. These effects were not accompanied by non-physiological phenomena such as hepatomegaly. Thus, these findings may be useful for better understanding fibrate action in humans.