Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy.

Jiaji Hu,Hanglu Ying,Jie Yao,Longhe Yang,Long Li,Huabin Ma,Yufen Zhao,Wenhui Jin

doi:10.3389/fphar.2021.744483

Abstract

Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

Highlights

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), which has been one of the severest causes of liver disorder all over the world
methionine- and cholinedeficient (MCD) diet greatly induced the increase of plasma Alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels, while PEA significantly decreased the levels of these biomarkers of liver function (Figures 1F–H)
The results showed that N-acylethanolaminehydrolyzing acid amidase (NAAA) expression in the MCD group is higher than that in the Ctrl group and a reduced expression was observed in the PEA group, but these differences were not statistically significant (Supplementary Figure S1E)

Summary

Introduction

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), which has been one of the severest causes of liver disorder all over the world. Inflammatory response has been identified as one of the key mediators in the progress of NASH (Schuster et al, 2018). The resident macrophages in the liver, are usually activated to the pro-inflammatory condition upon the stimulation of pathogen-associated molecular patterns or damage-associated molecular patterns during the development of NASH (Huang et al, 2010). Activated Kupffer cells could secrete numerous pro-inflammatory cytokines and chemokines and recruit an increasing number of circulating monocytes into the injured liver, resulting in hepatic inflammation and aggravated steatohepatitis (Zhang et al, 2019). As the activation of NLRP3 inflammasome is closely related to the progression of NASH, the strategy to suppress NLRP3 activation has been an efficient option to prevent NASH development (Mridha et al, 2017; Huang et al, 2021)

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Results

Conclusion