Heme oxygenase-1 alleviated non-alcoholic fatty liver disease via suppressing ROS-dependent endoplasmic reticulum stress

Li, Dongdong; Zhao, Dongzhi; Du, Jinghua; Dong, Shiming; Aldhamin, Zaid; Yuan, Xiwei; Li, Wencong; Du, Huijuan; Zhao, Wen; Cui, Luyao; Liu, Lingdi; Fu, Na; Nan, Yuemin

doi:10.1016/j.lfs.2020.117678

Cited by 36 publications

(24 citation statements)

References 40 publications

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“…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.…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2021

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Increased circulating levels of free fatty acids, especially saturated ones, are involved in disease progression in the non-alcoholic fatty liver. Although the mechanism of saturated fatty acid-induced toxicity in the liver is not fully understood, oxidative stress may be deeply involved. We examined the effect of increased palmitic acid, the most common saturated fatty acid in the blood, on the liver of BALB/c mice via tail vein injection with palmitate. After 24 h, among several anti-oxidative stress response genes, only heme oxygenase-1 (HO-1) was significantly upregulated in palmitate-injected mice compared with that in vehicle-injected mice. Elevation of HO-1 mRNA was also observed in the fatty liver of high-fat-diet-fed mice. To further investigate the role of HO-1 on palmitic acid-induced oxidative stress, in vitro experiments were performed to expose palmitate to HepG2 cells. SiRNA-mediated knockdown of HO-1 significantly increased the oxidative stress induced by palmitate, whereas pre-treatment with SnCl2, a well-known HO-1 inducer, significantly decreased it. Moreover, SB203580, a selective p38 inhibitor, reduced HO-1 mRNA expression and increased palmitate-induced oxidative stress in HepG2 cells. These results suggest that the HO-1-mediated anti-oxidative stress compensatory reaction plays an essential role against saturated fatty acid-induced lipotoxicity in the liver.

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Section: Discussionsupporting

confidence: 86%

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

et al. 2021

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“…Numerous chronic diseases are associated with ROS. Liver cirrhosis represents a condition in which oxidation and oxidation resistance are clearly imbalanced [6,7]. ROS are induced through the phosphoinositide 3-kinase (PI3K)/Akt pathway, which triggers various intracellular responses [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies

Rajendran

Ammar

Al-Saeedi

et al. 2020

IJMS

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In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated by reactive oxygen species (ROS). ZEA is a mycotoxin known to exert toxicity via inflammation and ROS accumulation. This study aims to explore the protective role of KFL against ZEA-triggered hepatic injury via the PI3K/Akt-regulated Nrf2 pathway. KFL augmented the phosphorylation of PI3K and Akt, which may stimulate antioxidative and antiapoptotic signaling in hepatic cells. KFL upregulated Nrf2 phosphorylation and the expression of antioxidant genes HO-1 and NQO-1 in a dose-dependent manner under ZEA-induced oxidative stress. Nrf2 knockdown via small-interfering RNA (siRNA) inhibited the KFL-mediated defence against ZEA-induced hepatotoxicity. In vivo studies showed that KFL decreased inflammation and lipid peroxidation and increased H2O2 scavenging and biochemical marker enzyme expression. KFL was able to normalize the expression of liver antioxidant enzymes SOD, CAT and GSH and showed a protective effect against ZEA-induced pathophysiology in the livers of mice. These outcomes demonstrate that KFL possesses notable hepatoprotective roles against ZEA-induced damage in vivo and in vitro. These protective properties of KFL may occur through the stimulation of Nrf2/HO-1 cascades and PI3K/Akt signaling.

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“…Our previous study ( 24 ) demonstrated that a HFD induces NASH in mice. Continuous feeding with a HFD triggers severe endoplasmic reticulum stress in the liver, and hepatocytes fail to adapt to this stress; they are unable to maintain normal homeostatic levels of unfolded or misfolded proteins, leading to hepatocyte apoptosis and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Co‑administration of obeticholic acid and simvastatin protects against high‑fat diet‑induced non‑alcoholic steatohepatitis in mice

Zhao

Ren

et al. 2021

Exp Ther Med

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Non-alcoholic steatohepatitis (NASH) has no approved therapy. The farnesoid X nuclear receptor (FXR) agonist obeticholic acid (OCA) has shown promise as a drug for NASH, but can adversely affect plasma lipid profiles. Therefore, the present study aimed to investigate the effects and underlying mechanisms of OCA in combination with simvastatin (SIM) in a high-fat diet (HFD)-induced model of NASH. C57BL/6J mice were fed with a HFD for 16 weeks to establish the NASH model. The mice were randomly divided into the following five groups: HFD, HFD + OCA, HFD + SIM, HFD + OCA + SIM and control. After 16 weeks, the mice were sacrificed under anesthesia. The ratios of liver weight to body weight (Lw/Bw) and of abdominal adipose tissue weight to body weight were calculated. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglycerides and low-density lipoprotein were measured. Liver sections were stained with hematoxylin and eosin. The protein levels of FXR, small heterodimeric partner (SHP) and cytochrome P450 family 7 subfamily A member 1 (CYP7A1) in the liver were detected by western blotting, while the mRNA levels of FXR, SHP, CYP7A1, bile salt export pump, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FASN) were examined by reverse transcription-quantitative polymerase chain reaction. The administration of OCA with or without SIM reduced the liver inflammation score compared with those of the HFD and HFD + SIM groups, with no significant difference between the HFD + OCA and HFD + OCA + SIM groups. The steatosis score followed similar trends to the inflammation score. In HFD-fed mice, OCA combined with SIM prevented body weight gain compared with that in HFD and HFD + OCA groups, and reduced the Lw/Bw ratio compared with that in the HFD and HFD + SIM groups. In addition to preventing HFD-induced increases of ALT and AST, the combination of OCA and SIM reduced the mRNA levels of IL-6, TNF-α, SREBP1 and FASN. On the basis of these results, it may be concluded that the strategy of combining OCA with SIM represents an effective pharmacotherapy for NASH.

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Heme oxygenase-1 alleviated non-alcoholic fatty liver disease via suppressing ROS-dependent endoplasmic reticulum stress

Cited by 36 publications

References 40 publications

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

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

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies

Co‑administration of obeticholic acid and simvastatin protects against high‑fat diet‑induced non‑alcoholic steatohepatitis in mice

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