Involvement of HO-1 and Autophagy in the Protective Effect of Magnolol in Hepatic Steatosis-Induced NLRP3 Inflammasome Activation In Vivo and In Vitro

Abstract

Magnolol (MG) is the main active compound of Magnolia officinalis and exerts a wide range of biological activities. In this study, we investigated the effects of MG using tyloxapol (Tylo)-induced (200 mg/kg, i.p.) hyperlipidemia in rats and palmitic acid (PA)-stimulated (0.3 mM) HepG2 cells. Our results showed that Tylo injection significantly increased plasma levels of triglyceride and cholesterol as well as superoxide anion in the livers, whereas MG pretreatment reversed these changes. MG reduced hepatic lipogenesis by attenuating sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) proteins and Srebp-1, Fas, Acc, and Cd36 mRNA expression as well as upregulated the lipolysis-associated genes Hsl, Mgl, and Atgl. Furthermore, MG reduced plasma interleukin-1β (IL-1β) and protein expression of NLR family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and caspase 1 as well as upregulated nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and induction of heme oxygenase-1 (HO-1) in hepatocytes of Tylo-treated rats. Enhanced autophagic flux by elevation of autophagy related protein 5-12 (ATG5-12), ATG7, Beclin1, and microtubule-associated protein light chain 3 B II (LC3BII)/LC3BI ratio, and reduction of sequestosome-1 (SQSTM1/p62) and phosphorylation of mTOR was observed by MG administration. However, autophagy inhibition with 3-methyladenine (3-MA) in HepG2 cells drastically abrogated the MG-mediated suppression of inflammation and lipid metabolism. In conclusion, MG inhibited hepatic steatosis-induced NLRP3 inflammasome activation through the restoration of autophagy to promote HO-1 signaling capable of ameliorating oxidative stress and inflammatory responses.

Role of HO-1 against Saturated Fatty Acid-Induced Oxidative Stress in Hepatocytes

“…In this mouse experiment, we also found that one antioxidant enzyme, HO-1, responded to the increase in palmitic acid levels in the blood. This feature was reproduced in the liver of mice fed an HFD, and consistent with several reports that discuss the importance of HO-1 in other mouse models of fatty livers [ 25 , 26 , 27 , 28 ]. Therefore, to further investigate the relationship between HO-1 and oxidative stress, we performed experiments using HepG2 cells with palmitate exposure.…”

The effects of magnolol supplementation on growth performance, meat quality, oxidative capacity, and intestinal microbiota in broilers

“…The mechanism of bioactive compounds such as phenols, carotenoids, alkaloids, or sulfur to activate the Nrf2- Keap1 pathway was either through the direct induction of Nrf2 expression or through inhibition of the dimerization of Nrf2 and Keap1 or enhancement of the transcriptional activity of Nrf2 ( Fakhri et al, 2020 ). MAG, known as an antioxidant, has been shown to stimulate the expression of Nrf2 and HO-1 in hepatocytes and hepatic steatosis mice ( Kuo et al, 2020 ).…”

Ethyl pyruvate ameliorates heat stroke-induced multiple organ dysfunction and inflammatory responses by induction of stress proteins and activation of autophagy in rats

“…Induction of HSP70 has been reported to protect against HS-induced organ damage, which is associated with the activation of the autophagic process [9,30]. On the other hand, recent studies have revealed that regulation of the autophagy pathway is novel anti-inflammatory targets of HO-1 [12,42]. By induction of autophagy, HO-1 protects against hepatocyte cell death and liver injury from infection/ sepsis in mice [43].…”