Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress.

Yun Ji,Hong Chen,Yue Yin,Yuan Gao,Weizhen Zhang

doi:10.3390/nu11092062

Abstract

Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty liver disease (NAFLD) from an in vivo study is lacking. In this study, we assessed the role of IAA in attenuating high-fat diet (HFD)-induced NAFLD in male C57BL/6 mice. Administration of IAA (50 mg/kg body weight) by intraperitoneal injection was found to alleviate HFD-induced elevation in fasting blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index as well as plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), and glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented the protective effect of IAA on liver damage induced by HFD feeding. HFD-induced an increase in liver total triglycerides and cholesterol, together with the upregulation of genes related to lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase 1 (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase 1 (Acaca), and glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated by IAA treatment. The results of reactive oxygen species (ROS) and malonaldehyde (MDA) level along with superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissue evidenced the protection of IAA against HFD-induced oxidative stress. Additionally, IAA attenuated the inflammatory response of liver in mice exposed to HFD as shown by the reduction in the F4/80-positive macrophage infiltration and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). In conclusion, our findings uncover that IAA alleviates HFD-induced hepatotoxicity in mice, which proves to be associated with the amelioration in insulin resistance, lipid metabolism, and oxidative and inflammatory stress.

Highlights

IntroductionNonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis on liver biopsy that is not initiated by alcohol consumption or other reasons (e.g., drugs, toxins, infections) [2]
Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, has been known to be inherently associated with obesity, insulin resistance, and dyslipidemia [1].NAFLD is defined as the presence of hepatic steatosis on liver biopsy that is not initiated by alcohol consumption or other reasons [2]
Liver damage was evaluated by the content of plasma glutamic-pyruvic transaminase (GPT) and glutamic oxalacetic transaminase (GOT)

Summary

Introduction

NAFLD is defined as the presence of hepatic steatosis on liver biopsy that is not initiated by alcohol consumption or other reasons (e.g., drugs, toxins, infections) [2]. The prevalence rate of NAFLD is estimated to be 24% around the world, among which 5–20% of patients with simple steatosis progress to nonalcoholic steatohepatitis (NASH) [3,4]. NASH is characterized by steatosis with lobular inflammation and the ballooning of hepatocytes, and increased risk of fibrosis, cirrhosis, and hepatocellular carcinoma [5]. The precise mechanisms related to NAFLD pathology are not completely elucidated, a multiple-hit Insulin resistance and overloading of lipids in hepatocytes result in steatosis, oxidative damage, and inflammation in liver tissue [8,9]

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Conclusion