Adaption of oxidative phosphorylation machinery compensates for hepatic lipotoxicity in early stages of MAFLD [hepatocyte]
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ABSTRACT:
PROVIDER: PRJNA814057 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.
2022-06-21 | GSE198173 | GEO
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032214 | Pride
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032211 | Pride
Project description:Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.
| S-EPMC9224893 | biostudies-literature
Project description:Background & Aims: Metabolic dysfunction associated steatotic liver disease (MAFLD) progresses to steatohepatitis (MASH) and is a major cause of liver cirrhosis. In the early disease stage, liver inflammation is absent. However, the early involvement of the peripheral immune cell compartments in disease progression is poorly understood and single cell profiles of peripheral immune cells in MAFLD/MASH are not known. Methods: MAFLD/MASH patients and healthy volunteers have been prospectively enrolled into a cross-sectional study. Patients have been histologically stratified and characterized by liver bulk RNA-Seq.
2025-04-30 | GSE267031 | GEO
Project description:Background & Aims: Metabolic dysfunction associated steatotic liver disease (MAFLD) progresses to steatohepatitis (MASH) and is a major cause of liver cirrhosis. In the early disease stage, liver inflammation is absent. However, the early involvement of the peripheral immune cell compartments in disease progression is poorly understood and single cell profiles of peripheral immune cells in MAFLD/MASH are not known. Methods: MAFLD/MASH patients and healthy volunteers have been prospectively enrolled into a cross-sectional study characterized by White Blood bulk RNA-Seq.
2025-04-30 | GSE267032 | GEO
Project description:Transcriptomic analysis was applied to liver tissues of seven patients with MAFLD and nine normal controls,then, differential genes were identified by comparative analysis of sequencing results, and target genes that may be related to the pathogenesis of MAFLD were further studied.This study may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.
2021-12-14 | GSE183229 | GEO
Project description:MAFLD is a heterogenous spectrum disorder affecting 20% of the population. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as an approach to mitigating liver fibrosis. Lipopolysaccharide binding protein is a secreted protein that plays an established role in innate immune responses. In a murine model of MAFLD, we used a liver-specific deletion of LBP model to study its role in hepatic inflammation. Single nucleus RNA-seq were applied to investigate the role of LBP in hepatic cell composition.
2024-07-15 | GSE254626 | GEO
Project description:Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.
2025-02-13 | GSE289495 | GEO