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

这项研究考察了临床相关的小剂量贝特类药物对饮食诱导的肝骨质疏松症小鼠肝脏脂代谢的影响。小剂量贝特类通过增强肝脏线粒体脂肪酸β-氧化功能来减少脂肪变性，这不是由于已知的PPARpha激活所致。这种新的药理作用似乎与提高β-氧化酶的蛋白质稳定性有关，这可能是由于心磷脂的含量增加，这是一种线粒体特有的磷脂，对线粒体蛋白质的稳定性/功能很重要。这些效应并不伴随肝肿大等非生理性现象。因此，这些发现可能有助于更好地理解贝特类药物在人体内的作用。

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.