Division of Endocrinology, Diabetes, and Nutrition , Department of Medicine , University of Maryland School of Medicine , Baltimore , Maryland , USA.
Genomics Core , National Institute of Diabetes and Digestive and Kidney Disease , National Institutes of Health , Bethesda , Maryland , USA.
Hepatology. 2023 May 1;77(5):1688-1701. doi: 10.1002/hep.32675. Epub 2023 Apr 17.
Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis.
Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration.
Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.
酒精相关性肝病（ALD）的病理学包括脂肪变性、炎症和损伤，这些病变可能进展为纤维化、肝硬化和癌症。肝脏从脂肪组织三酰甘油水解中接收约 60%的脂肪酸，但在任何选择性失活脂肪分解的遗传动物模型中，尚未直接研究这种脂肪分解途径在 ALD 发展中的作用。
利用脂肪组织特异性比较基因鉴定-58（CGI-58）敲除（FAT-KO）小鼠，即脂肪分解受损的模型，我们发现，当用国家酒精滥用和酒精中毒研究所慢性和 binge 乙醇喂养模型处理时，缺乏脂肪分解的小鼠几乎完全免受乙醇诱导的肝脂肪变性和脂质过氧化的影响。这不太可能是由于脂质合成减少所致，因为这种乙醇喂养方案在两种基因型中相似地下调了肝内脂质生成基因的表达。在等热量喂养组中，与对照小鼠相比，FAT-KO 小鼠的肝细胞损伤、中性粒细胞浸润和转录因子信号转导和转录激活因子 3（STAT3）在肝脏中的激活增加；而这些在乙醇喂养中都没有加重。STAT3 的激活与肝瘦素受体 mRNA 表达和脂肪组织炎性细胞浸润的显著增加有关。
我们的研究结果确立了脂肪分解在驱动 ALD 发展过程中的肝脂肪变性和氧化应激中的关键作用。
