Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Hepatol. 2011 Mar;54(3):432-8. doi: 10.1016/j.jhep.2010.07.039. Epub 2010 Sep 22.
BACKGROUND & AIMS: Disturbance in lipid metabolism is one of the features of chronic hepatitis C, being a crucial determinant of the progression of liver fibrosis. Experimental studies have revealed that the core protein of hepatitis C virus (HCV) induces steatosis.
The activities of fatty acid metabolizing enzymes were determined by analyzing the fatty acid compositions in HepG2 cells with or without core protein expression.
There was a marked accumulation of triglycerides in core-expressing HepG2 cells. While the oleic/stearic acid (18:1/18:0) and palmitoleic/palmitic acid ratio (16:1/16:0) were comparable in both the core-expressing and the control cells, there was a marked accumulation of downstream product, 5,8,11-eicosatrienoic acid (20:3(n-9)) in the core-expressing HepG2 cells. The addition of eicosatetraynoic acid, which inhibits delta-6 desaturase activity which is inherently high in HepG2 cells, led to a marked accumulation of oleic and palmitoleic acids in the core-expressing cells, showing that delta-9 desaturase was activated by the core protein. Eicosapentaenoic acid (20:5(n-3)) or arachidonic acid (20:4(n-6)) administration significantly decreased delta-9 desaturase activity, the concentration of 20:3(n-9), and triglyceride accumulation. This lipid metabolism disorder was associated with NADH accumulation due to mitochondrial dysfunction, and was reversed by the addition of pyruvate through NADH utilization.
The fatty acid enzyme, delta-9 desaturase, was activated by HCV core protein and polyunsaturated fatty acids counteracted this impact of the core protein on lipid metabolism. These results may open up new insights into the mechanism of lipid metabolism disorder associated with HCV infection and provide clues for the development of new therapeutic devices.
脂质代谢紊乱是慢性丙型肝炎的特征之一，是肝纤维化进展的重要决定因素。实验研究表明，丙型肝炎病毒（HCV）的核心蛋白可诱导脂肪变性。
通过分析表达或不表达核心蛋白的 HepG2 细胞中的脂肪酸组成，测定脂肪酸代谢酶的活性。
在表达核心蛋白的 HepG2 细胞中，甘油三酯明显积聚。虽然在表达核心蛋白的细胞和对照细胞中，油酸/硬脂酸（18:1/18:0）和棕榈油酸/棕榈酸比值（16:1/16:0）相似，但下游产物 5,8,11-二十碳三烯酸（20:3(n-9))在表达核心蛋白的 HepG2 细胞中明显积聚。添加二十碳三烯酸，可抑制固有高活性的Δ6 去饱和酶，导致表达核心蛋白的细胞中油酸和棕榈油酸明显积聚，表明Δ9 去饱和酶被核心蛋白激活。二十碳五烯酸（20:5(n-3))或花生四烯酸（20:4(n-6))给药可显著降低Δ9 去饱和酶活性、20:3(n-9)浓度和甘油三酯积聚。这种脂质代谢紊乱与线粒体功能障碍导致的 NADH 积累有关，通过利用 NADH 添加丙酮酸可逆转这种情况。
HCV 核心蛋白激活脂肪酸酶Δ9 去饱和酶，多不饱和脂肪酸可拮抗核心蛋白对脂质代谢的影响。这些结果可能为丙型肝炎病毒感染相关脂质代谢紊乱的机制提供新的见解，并为新的治疗手段的开发提供线索。
