The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Gabbia, Daniela; Cannella, Luana; Martin, Sara De

doi:10.3390/biomedicines9060687

Cited by 63 publications

(60 citation statements)

References 85 publications

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“…ROS can induce the proliferation and migration of HSCs, collagen accumulation, and the formation of liver fibrosis [67,68]. NADPH oxidase 4 (NOX4)-derived ROS are the main source of oxidative stress in NAFLD, and they contribute to hepatic injury [69]. In the present study, a high-fat diet upregulated the protein expression of NOX4, with high levels of superoxide anion production and MDA observed in the zebrafish liver.…”

Section: Discussionmentioning

confidence: 50%

Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

Zou

Chen

Sun

et al. 2021

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a common disease that causes serious liver damage. Exercise is recognized as a non-pharmacological tool to improve the pathology of NAFLD. However, the antioxidative effects and mechanisms by which exercise ameliorates NAFLD remain unclear. The present study conducted exercise training on zebrafish during a 12-week high-fat feeding period to study the antioxidant effect of exercise on the liver. We found that swimming exercise decreased lipid accumulation and improved pathological changes in the liver of high-fat diet-fed zebrafish. Moreover, swimming alleviated NOX4-derived reactive oxygen species (ROS) overproduction and reduced methanedicarboxylic aldehyde (MDA) levels. We also examined the anti-apoptotic effects of swimming and found that it increased the expression of antiapoptotic factor bcl2 and decreased the expression of genes associated with apoptosis (caspase3, bax). Mechanistically, swimming intervention activated SIRT1/AMPK signaling-mediated lipid metabolism and inflammation as well as enhanced AKT and NRF2 activation and upregulated downstream antioxidant genes. In summary, exercise attenuates pathological changes in the liver induced by high-fat diets. The underlying mechanisms might be related to NRF2 and mediated by SIRT1/AMPK signaling.

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Section: Discussionmentioning

confidence: 50%

Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

Zou

Chen

Sun

et al. 2021

IJMS

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“…Since oxidative stress plays a pivotal role in fibrogenesis and it has been demonstrated that OC displays antioxidant effect on various cell lines ( 5 ), we investigated its effect on oxidative stress-related pathways. Investigating oxidative stress is of particular relevance in fibrosis, since it well known that the pro-oxidative activity of the NOXs is increasing upon the activation of the receptor for advanced glycation endproducts (RAGE), caused by its interaction with ligands induced during inflammation ( 11 ). Beside NOXs, RAGE can in turn activate the inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, leading to a vicious cycle in which oxidative stress and inflammation generate a sustained pro-fibrotic response by reciprocal synergic actions ( 11 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…Investigating oxidative stress is of particular relevance in fibrosis, since it well known that the pro-oxidative activity of the NOXs is increasing upon the activation of the receptor for advanced glycation endproducts (RAGE), caused by its interaction with ligands induced during inflammation ( 11 ). Beside NOXs, RAGE can in turn activate the inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, leading to a vicious cycle in which oxidative stress and inflammation generate a sustained pro-fibrotic response by reciprocal synergic actions ( 11 , 43 ). In this context, we first observed that OC treatment downregulated the mRNA expression of two isoforms of NOXs i.e., NOX1 and NOX4, peculiar enzymes involved in hepatic ROS production, in TGF-β1-activated LX2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Liver fibrosis represents the outcome of wound-healing response occurring in chronic liver diseases of different etiologies. Fibrosis can progress into liver cirrhosis which in turn may lead to liver failure and cancer ( 11 ). According to the Global Burden of Disease, chronic liver diseases are accounted as one of the major causes of mortality in the world, with more than 1.32 millions of deaths only in 2017 ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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The Extra Virgin Olive Oil Polyphenol Oleocanthal Exerts Antifibrotic Effects in the Liver

et al. 2021

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Liver fibrosis, which is the outcome of wound-healing response to chronic liver damage, represents an unmet clinical need. This study evaluated the anti-fibrotic and anti-inflammatory effects of the polyphenol oleocanthal (OC) extracted from extra virgin olive oil (EVOO) by an in vitro/in vivo approach. The hepatic cell lines LX2 and HepG2 were used as in vitro models. The mRNA expression of pro-fibrogenic markers, namely alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 chain (COL1A1), a panel of metalloproteinases (MMP1, MMP2, MMP3, MMP7, MMP9) and vascular endothelial growth factor A (VEGFA) as well as the pro-oxidant genes NADPH oxidases (NOXs) 1 and 4 were evaluated in TGF-β activated LX2 cells by qRT-PCR. α-SMA and COL1A1 protein expression was assessed by immunofluorescence coupled to confocal microscopy. VEGFA release from LX2 was measured by ELISA. We also evaluated the amount of reactive oxygen species (ROS) produced by H2O2 activated- HepG2 cells. In vivo, OC was administered daily by oral gavage to Balb/C mice with CCl4-induced liver fibrosis. In this model, we measured the mRNA hepatic expression of the three pro-inflammatory interleukins (IL) IL6, IL17, IL23, chemokines such as C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 12 (CXCL12), and selected miRNAs (miR-181-5p, miR-221-3p, miR-29b-3p and miR-101b-3p) by qRT-PCR. We demonstrated that OC significantly downregulated the gene/protein expression of α-SMA, COL1A1, MMP2, MMP3, MMP7 and VEGF as well as the oxidative enzymes NOX1 and 4 in TGFβ1-activated LX2 cells, and reduced the production of ROS by HepG2. In vivo OC, beside causing a significant reduction of fibrosis at histological assessment, counteracted the CCl4-induced upregulation of pro-fibrotic and inflammatory genes. Moreover, OC upregulated the anti-fibrotic miRNAs (miR-29b-3p and miR-101b-3p) reduced in fibrotic mice, while downregulated the pro-fibrotic miRNAs (miR-221-3p and miR-181-5p), which were dramatically upregulated in fibrotic mice. In conclusion, OC exerts a promising antifibrotic effect via a combined reduction of oxidative stress and inflammation involving putative miRNAs, which in turn reduces hepatic stellate cells activation and liver fibrosis.

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“…It should be noticed that the lack of HNF4α in the liver seems to be associated with impaired lipid, glucose, cholesterol, and BA homeostasis and is considered as a pivotal regulator of hepatic transcriptome. Some of the genes downregulated in HNF4α-liver knockout mice in a male-specific manner are Cyp7b1, involved in the synthesis of BAs, Hsd3b4 (hydroxysteroid dehydrogenase 4), and Nox4 (NADPH oxidase 4), involved in oxidative stress [ 110 , 111 ].…”

Section: Pxr-related Gender Differences In Chronic Liver Diseasementioning

confidence: 99%

The Nuclear Receptor PXR in Chronic Liver Disease

Sayaf

Zanotto

Russo

et al. 2021

Cells

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Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

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The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Cited by 63 publications

References 85 publications

Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

The Extra Virgin Olive Oil Polyphenol Oleocanthal Exerts Antifibrotic Effects in the Liver

The Nuclear Receptor PXR in Chronic Liver Disease

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