Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases

Mooli, Raja Gopal Reddy; Mukhi, Dhanunjay; Ramakrishnan, S

doi:10.1002/cphy.c200021

Cited by 35 publications

(18 citation statements)

References 456 publications

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“…In support, hepatic ketogenesis is found to be augmented initially with HFD ( Sunny et al, 2010 ) when insulin levels are higher, and insulin sensitivity is intact. However, prolonged exposure to HFD progressively decrease ketogenesis ( Asif et al, 2022 ), which is temporally linked with insulin resistance and compounded by other conditions such as oxidative stress and mitochondrial damage ( Mooli et al, 2022 ). But how insulin resistance affects hepatic ketogenesis?…”

Section: Hepatic Ketogenesis and Non-alcoholic Steatohepatitismentioning

confidence: 99%

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

Mooli

Ramakrishnan

2022

Front. Physiol.

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Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from β-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.

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Section: Hepatic Ketogenesis and Non-alcoholic Steatohepatitismentioning

confidence: 99%

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

Mooli

Ramakrishnan

2022

Front. Physiol.

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“…The increased production of ROS leads to molecular damage called oxidative stress, and NAFLD is influenced by a “multiple parallel-hit model” in which oxidative stress plays a central role. 30 Our results showed that overexpression of LINC00240 did not affect lipid accumulation but increased ROS content in HepG2 cells. This suggested that LINC00240 may have an effect on oxidative stress in hepatocytes.…”

Section: Discussionmentioning

confidence: 53%

“…We explored the function of LINC00240 in NAFLD in the HepG2 NAFLD model. The increased production of ROS leads to molecular damage called oxidative stress, and NAFLD is influenced by a “multiple parallel-hit model” in which oxidative stress plays a central role . Our results showed that overexpression of LINC00240 did not affect lipid accumulation but increased ROS content in HepG2 cells.…”

Section: Discussionmentioning

confidence: 61%

Identify Functional lncRNAs in Nonalcoholic Fatty Liver Disease by Constructing a ceRNA Network

et al. 2022

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Aim : To identify functional long noncoding RNAs (lncRNAs) by constructing a NAFLD-related lncRNA–miRNA–mRNA network (NLMMN) based on the hypothesis that lncRNAs, as competitive endogenous RNAs (ceRNAs), are able to regulate mRNA functions by competitive binding to shared miRNAs. Methods : The “Limma R package” was used to identify differentially expressed lncRNAs and mRNAs (DElncRNAs and DEmRNAs). The “miRcode online tool” was used to predict the potential interactions between DElncRNAs or DEmRNAs using Perl, and “multiMiR R package” was used to predict the potential interactions between DElncRNAs and miRNAs. The NLMMN was viewed by Cytoscape. The DEmRNAs were further analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The real-time quantitative reverse transcription polymerase chain reaction (qRT–PCR) was used to identify functional lncRNAs in human liver tissue and FFAs-induced fat-overloading HepG2 cells. The role of functional lncRNA was explored in the HepG2 cell line. Results : A total of 336 DElncRNAs (154 upregulated and 182 downregulated, |log 2 (fold change) |>0.655 and P < 0.05) and 399 DEmRNAs (152 upregulated and 247 downregulated, |log 2 (fold change) |>0.608 and P < 0.05) were identified. A total of 142 DElncRNA-miRNA interaction pairs and 643 miRNA–DEmRNA interaction pairs were retained to construct the NLMMN, which contained 19 lncRNAs, 47 miRNAs, and 228 mRNAs. The results of GO and KEGG enrichment analyses were related to an extracellular matrix (ECM). Two upregulated lncRNAs (LINC00240 and RBMS3-AS3) and one downregulated lncRNA (ALG9-IT1) were identified by qRT–PCR in liver tissues. But only LINC00240 was significantly upregulated in fat-overloading HepG2 cells. Overexpression of LINC00240 did not affect lipid accumulation but increased the reactive oxygen species (ROS) content in HepG2 cells. Conclusion : LINC00240, RBMS3-AS3, and ALG9-IT1 might be novel functional lncRNAs that attenuate liver fibrosis in NAFLD by influencing the ECM through the ceRNA network. Among them, LINC00240 might have a key role.

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“…A previous study reported that Con A treatment increased liver‐specific ROS, leading to damage associated with oxidative stress in the liver 54 . Oxidative stress plays an important role in liver disease development 55,56 . Namely, MDA is a marker of lipid peroxidation in membranes, and MDA levels in the liver were previously reported to increase with Con A treatment 57 .…”

Section: Discussionmentioning

confidence: 97%

Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

Zhang,

Cheng,

Zhang

et al. 2024

The FASEB Journal

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Immune‐mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin‐28A (IL‐28A), a member of the IL‐10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL‐28A, its role in immune‐mediated acute injury remains unclear. The present study investigated the role of IL‐28A in concanavalin A (Con A)‐induced acute immune liver injury. After Con A injection in mice, IL‐28A level significantly increased. IL‐28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL‐28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL‐28A‐deficiency group than in the wild‐type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL‐28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐12, IL‐6, and IL‐1β, by M1 macrophages decreased significantly in the IL‐28A‐deficiency group. Western blotting demonstrated that IL‐28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)‐κB, mitogen‐activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL‐28A deletion plays an important protective role in the Con A‐induced acute liver injury model and IL‐28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF‐κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune‐related hepatic injury.

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Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases

Cited by 35 publications

References 456 publications

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease

Identify Functional lncRNAs in Nonalcoholic Fatty Liver Disease by Constructing a ceRNA Network

Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

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