Imai Yumi, Varela Gladys M, Jackson Malaka B, Graham Mark J, Crooke Rosanne M, Ahima Rexford S
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19010, USA.
Gastroenterology. 2007 May;132(5):1947-54. doi: 10.1053/j.gastro.2007.02.046. Epub 2007 Feb 23.
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action.
Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined.
ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice.
This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.
非酒精性脂肪性肝病（NAFLD）的特征是肝细胞内甘油三酯过度蓄积。在NAFLD中，脂滴蛋白脂肪分化相关蛋白（ADRP）的表达增加，但这是否与肝脏脂质代谢存在因果关系尚不清楚。我们推测，ADRP的减少将改善肝脏脂肪变性并改善胰岛素作用。
用针对ADRP的反义寡核苷酸（ASO）处理瘦素缺乏的Lep(ob/ob)小鼠和饮食诱导肥胖（DIO）小鼠，并检测其对肝脏和血清脂质以及葡萄糖稳态的影响。
ADRP ASO特异性降低了Lep(ob/ob)和DIO小鼠肝脏中ADRP的mRNA和蛋白质水平，而未改变其他脂滴蛋白（即S3-12和TIP47）的水平。ADRP ASO抑制了脂肪生成基因的表达，降低了肝脏甘油三酯含量而不影响胆固醇，减弱了甘油三酯分泌，并降低了血清甘油三酯和丙氨酸转氨酶水平。ADRP ASO减轻肝脏脂肪变性与Lep(ob/ob)和DIO小鼠葡萄糖稳态的改善有关。
本研究证明了脂滴蛋白ADRP在脂质代谢调节中的关键作用。使用反义寡核苷酸降低肝脏ADRP水平可逆转肥胖小鼠的肝脏脂肪变性、高甘油三酯血症和胰岛素抵抗，提示ADRP可能是治疗NAFLD及相关脂质和葡萄糖异常的靶点。
