Pan Zhen-Guo, An Xu-Sheng
Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China.
Intensive Care Unit, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China.
Biochem Biophys Res Commun. 2018 Apr 6;498(3):416-423. doi: 10.1016/j.bbrc.2018.02.115. Epub 2018 Feb 15.
SARM1 (Sterile alpha and armadillo motif-containing protein 1) is the recently identified TIR domain-containing cytosolic protein, which is involved in toll-like receptors (TLRs) signaling transduction. In the present study, the role of SARM1 in high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) progression was explored. We found that SARM1 was expressed highly in fatty liver. And SARM1-knockout (KO) reduced steatohepatitis and metabolic disorders induced by HFD. SARM1-deletion decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in HFD-fed mice. Additionally, inflammatory response caused by HFD was alleviated by SARM1-deletion through inactivating TLR4/7/9 and nuclear factor kappa B (NF-κB) pathways. Of note, SARM1-deletion also reduced the expressions of inflammation-associated molecules in hypothalamus of HFD-fed mice. Furthermore, HFD administration led to oxidative stress in liver of mice, while being decreased in SARM1-KO mice. Moreover, SARM1-ablation improved lipid dyslipidemia by suppressing the mRNA levels of genes, linked to glycolysis, lipogenesis and transcriptional regulation. Insulin resistance was also attenuated by SARM1-deficiency through enhancing the activation of liver Akt/glycogen synthase kinase-3β (GSK3β) and insulin receptor substrate-1 (IRS1)/FOXO1 pathways in HFD-fed mice. Also, SARM1-knockout improved neuropeptide Y (NPY), Pro-Opiomelanocortins (POMC), Agouti-related Protein (AGRP) and Cocaine-and-Amphetamine Responsive Transcript 1 (CART1) expressions in hypothalamus of mice after HFD administration. In vitro, we found that the reduction of inflammatory response, oxidative stress and dyslipidemia induced by SARM1-knockout in primary hepatocytes after fructose stimulation was largely attributed to its suppression to TLR4/7/9. Together, the findings demonstrated that SARM1 might be an effective target for developing effective therapeutic strategies against NAFLD.
SARM1（含无菌α和犰狳基序蛋白1）是最近鉴定出的含TIR结构域的胞质蛋白，参与Toll样受体（TLR）信号转导。在本研究中，探讨了SARM1在高脂饮食（HFD）诱导的非酒精性脂肪性肝病（NAFLD）进展中的作用。我们发现SARM1在脂肪肝中高表达。SARM1基因敲除（KO）减轻了HFD诱导的脂肪性肝炎和代谢紊乱。SARM1缺失降低了HFD喂养小鼠的天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平。此外，SARM1缺失通过使TLR4/7/9和核因子κB（NF-κB）信号通路失活，减轻了HFD引起的炎症反应。值得注意的是，SARM1缺失还降低了HFD喂养小鼠下丘脑炎症相关分子的表达。此外，HFD给药导致小鼠肝脏氧化应激，而在SARM1-KO小鼠中氧化应激降低。此外，SARM1缺失通过抑制与糖酵解、脂肪生成和转录调控相关基因的mRNA水平，改善了脂质代谢异常。在HFD喂养的小鼠中，SARM1缺失还通过增强肝脏Akt/糖原合酶激酶-3β（GSK3β）和胰岛素受体底物-1（IRS1）/叉头框蛋白O1（FOXO1）信号通路的激活，减轻了胰岛素抵抗。此外，SARM1基因敲除改善了HFD给药后小鼠下丘脑神经肽Y（NPY）、阿黑皮素原（POMC）、刺鼠相关蛋白（AGRP）和可卡因及苯丙胺调节转录肽1（CART1）的表达。在体外，我们发现果糖刺激后原代肝细胞中SARM1基因敲除诱导的炎症反应、氧化应激和脂质代谢异常的减轻主要归因于其对TLR4/7/9的抑制作用。总之，这些发现表明SARM1可能是开发针对NAFLD有效治疗策略的有效靶点。
