Department of Medicine Washington University School of Medicine St. Louis, MO, USA.
Hepatology. 2012 Nov;56(5):1995-8. doi: 10.1002/hep.26088.
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.
非酒精性脂肪性肝病（NAFLD）与心血管和肝脏相关死亡率的增加有关。NAFLD 的特征是甘油三酯和游离胆固醇（FC）的积累，而胆固醇酯没有相应增加。本研究的目的是评估 NAFLD 中胆固醇代谢基因的表达，并将这些与疾病表型相关联。NAFLD 与 SREBP-2 成熟、HMG CoA 还原酶（HMGCR）表达增加和 HMGCR 磷酸化减少有关。通过循环去甲胆固醇：胆固醇比值测量，胆固醇合成增加。在 NAFLD 中增加的 microRNA-34a 抑制了 sirtuin-1，导致 AMP 激酶和 HMGCR 的去磷酸化。胆固醇酯水解酶增加，而 ACAT-2 保持不变。LDL 受体表达显著降低，且在服用或未服用他汀类药物的 NAFLD 患者中相似。HMGCR 表达与 FC、NAFLD 的组织学严重程度和 LDL-胆固醇相关。这些数据表明，NAFLD 中的胆固醇代谢失调可能导致疾病严重程度和心血管风险增加。
