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

• Project/Area Number: 23790178
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Shinshu University
• Principal Investigator: NAKAJIMA Takero 信州大学, 医学系研究科, 助教 (30581011)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脂質代謝 / 脂肪酸代謝 / ミトコンドリアβ酸化 / 臨床用量 / 分子薬理学

Research Abstract

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.