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Biochem Biophys Res Commun. 2018 Apr 6;498(3):416-423. doi: 10.1016/j.bbrc.2018.02.115. Epub 2018 Feb 15.

SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation.

Author information

1
Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China.
2
Intensive Care Unit, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, PR China. Electronic address: 848864017@qq.com.

Abstract

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.

KEYWORDS:

Dyslipidemia; Inflammation; NAFLD; Oxidative stress; SARM1

PMID:
29454967
DOI:
10.1016/j.bbrc.2018.02.115
[Indexed for MEDLINE]

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