Cell Metab：研究揭示非酒精性脂肪肝患者胆固醇代谢异常

近日，来自弗吉尼亚联邦大学的研究者通过研究发现了病人机体中异常胆固醇生产和代谢的分子改变，这或许可以解释病人肝脏疾病的严重性以及患者心脏健康的风险。据估计，三分之一的美国人都有脂肪肝，非酒精性脂肪肝是一种常见的肝脏疾病，和心脏及肝脏致死风险的增加直接相关。

研究者们的发现或可以提供潜在的治疗靶点，而且可以使临床医生更深入地评估心脏血管疾病的风险以及发明出新的方法来降低个体NASH发病的风险。这项研究成果刊登在了国际杂志Cell Metabolism上。研究小组表示，并不仅仅是机体中胆固醇产量的增加，而且还包括血液中吸收胆固醇受体表达的降低，因此肝脏中增加的胆固醇的输出，并且进入血液，导致引发心血管疾病，一般来讲，肝脏不仅仅可以产生胆固醇，也可以从血液中吸收过多的胆固醇。

研究者Arun表示，他们的研究揭示了在脂肪肝病人的肝脏中会产生过多的胆固醇，因此这就很容易引发肝脏硬化以及增加患者心脏疾病的风险。相关研究由美国国立卫生研究院支持。 

doi:10.1016/j.cmet.2012.04.004
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Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease

Hae-Ki Min, Ashwani Kapoor, Michael Fuchs, Faridoddin Mirshahi, Huiping Zhou, James Maher, John Kellum, Russell Warnick, Melissa J. Contos, Arun J. Sanyal

Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks.