Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, ACT, Australia.
Lab Invest. 2019 Jan;99(1):4-16. doi: 10.1038/s41374-018-0120-x. Epub 2018 Sep 26.
Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.
非酒精性脂肪性肝炎（NASH）是一种可发展为肝硬化的非酒精性脂肪性肝病。实现体重减轻 10%的生活方式改变可逆转 NASH，但目前尚无有效的批准药物治疗。我们之前发现适应性产热缺陷是导致代谢综合征和肝脂肪变性的一个因素。我们现在已经测试了增加非颤抖性产热是否可以改善小鼠的现有 NASH。在高脂肪饮食喂养的 foz/foz 小鼠中，β3AR 激动剂治疗恢复了棕色脂肪组织（BAT）的功能，与未治疗的对照组相比，体重减轻，葡萄糖耐量改善，肝脂质含量降低，但对肝炎症或非酒精性脂肪性肝病活动评分（NAS）没有影响。同样，β3AR 激动剂在其他脂肪性肝炎模型中，包括 MCD 饮食喂养的糖尿病肥胖 db/db 小鼠中，也没有改变肝病理学。单独热量限制可减轻 foz/foz 小鼠的肝炎症特征。在接受热量限制的小鼠中添加 β3AR 激动剂可增强体重减轻和葡萄糖耐量，并改善肝脂肪变性、肝细胞损伤，并进一步减少肝炎症。这些变化导致 NAS 评分显著降低，例如在这组中，没有（0/9）只动物符合 NASH 病理学标准，而单独热量限制的十只动物中有八只符合标准。总之，β3AR 激动剂可对抗代谢综合征的特征并减轻脂肪变性，但不能逆转 NASH。然而，当与减肥疗法结合使用时，BAT 刺激提供了额外的治疗优势并逆转了 NASH。
