Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.
Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.
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DOI：
10.1016/j.cmet.2012.04.004
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发表时间：
2012-05-02
期刊：
影响因子：
29
通讯作者：
Sanyal AJ
中科院分区：
文献类型：
--
作者：
Min HK;Kapoor A;Fuchs M;Mirshahi F;Zhou H;Maher J;Kellum J;Warnick R;Contos MJ;Sanyal AJ
非酒精性脂肪性肝病（NAFLD）与心血管和肝脏相关死亡率增加相关。NAFLD的特点是甘油三酯和游离胆固醇（FC）积累，而胆固醇酯没有相应的增加。本研究的目的是评估NAFLD中胆固醇代谢基因的表达及其与疾病表型的关系。NAFLD与SREBP-2成熟、HMG辅酶a还原酶（HMGCR）表达增加和HMGCR磷酸化降低有关。通过循环去氨甾醇：胆固醇比值测定，胆固醇合成增加。miR-34a，一个在NAFLD中升高的microRNA，通过AMP激酶和HMGCR的下游去磷酸化抑制sirtuin-1。胆固醇酯水解酶升高，而ACAT-2保持不变。LDL受体表达在服用或停用他汀类药物的NAFLD受试者中显著降低，且相似。HMGCR的表达与FC、NAFLD的组织学严重程度和ldl -胆固醇相关。这些数据表明，NAFLD中胆固醇代谢失调可能导致疾病严重程度和心血管风险。
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.
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DOI：
10.1161/01.atv.0000160613.57985.18
发表时间：
2005-05-01
影响因子：
8.7
作者：
Brea, A;Mosquera, D;Ros, E
通讯作者：
Ros, E
影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
2.2
作者：
Chalasani NP;Sanyal AJ;Kowdley KV;Robuck PR;Hoofnagle J;Kleiner DE;Unalp A;Tonascia J;NASH CRN Research Group
通讯作者：
NASH CRN Research Group
影响因子：
25.7
作者：
Adams, LA;Sanderson, S;Angulo, P
通讯作者：
Angulo, P
影响因子：
13.5
作者：
Feldstein, AE;Werneburg, NW;Gores, GJ
通讯作者：
Gores, GJ