Core liver homeostatic co-expression networks are preserved between mouse and human but respond to perturbations in an organism- and disease-specific manner
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148080 | GEO | 2021/05/05
REPOSITORIES: GEO
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Project description:Understanding mechanisms causing MAFLD (Metabolic Associated Fatty Liver Disease) and its progression to MASH (metabolic dysfunction-associated steatohepatitis) is clinically important and scientifically challenging. Hepatic insulin resistance is a common component in the progression of MAFLD in patients and experimental animals; however, hepatic steatosis caused by the HFD45% (high-fat diet) decreases during chronic hepatic IR generated by inactivation of Irs1/2 (LDKO), AKT1/2, or InsR 1-3—which is inconsistent with the expected relationship between IR and MAFLD in humans4. Here we found that complete hepatic insulin resistance promotes the fructose-enriched GAN diet-induced MAFLD, including acute inflammation and MASH in LDKO mice. Unexpectedly, fructose phosphorylation catalyzed by hepatic Khk (ketohexokinase) was not required as acute MAFLD progressed strongly in LDKOKhkL/L mice fed the GAN diet. FoxO1 activated during hepatic IR induces Fst (Follistatin) expression and secretion from the liver of LDKO mice. Inactivation of hepatic FoxO1 in LTKO mice (LDKO•FoxO1L/L) or Fst in LDKOFstKO mice prevented acute MAFLD during the GAN diet. Consistently, overexpression of hepatic Fst promoted GAN diet-induced MAFLD/MASH and hepatic carcinoma. Mechanistically, circulating Fst promoted adipose tissue IR and lipolysis, which can deliver FFA (free fatty acid) to the liver for esterification with excess Gro3P (glycerol 3-phosphate) generated by fructose metabolism, although hepatic DNL (de novo lipogenesis) decreased strongly in LDKO mice while. Since circulating FST correlates positively with both T2D and MAFLD in humans, our results suggests that hepatic FST induced by progressive hepatic IR might promote MAFLD/MASH during the consumption of sugar-sweetened food and beverages consumed frequently by people and animals with T2D.
2024-06-23 | GSE270246 | 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.
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Project description:The ability to predict which genes will respond to the perturbation of a transcription factor serves as a benchmark for our systems-level understanding of transcriptional regulatory networks. In previous work, machine learning models have been trained to predict static gene expression levels in a biological sample by using data from the same or similar samples, including data on their transcription factor binding locations, histone marks, or DNA sequence. We report on a different challenge-training machine learning models to predict which genes will respond to the perturbation of a transcription factor without using any data from the perturbed cells. We find that existing transcription factor location data (ChIP-seq) from human cells have very little detectable utility for predicting which genes will respond to perturbation of a transcription factor. Features of genes, including their preperturbation expression level and expression variation, are very useful for predicting responses to perturbation of any transcription factor. This shows that some genes are poised to respond to transcription factor perturbations and others are resistant, shedding light on why it has been so difficult to predict responses from binding locations. Certain histone marks, including H3K4me1 and H3K4me3, have some predictive power when located downstream of the transcription start site. However, the predictive power of histone marks is much less than that of gene expression level and expression variation. Sequence-based or epigenetic properties of genes strongly influence their tendency to respond to direct transcription factor perturbations, partially explaining the oft-noted difficulty of predicting responsiveness from transcription factor binding location data. These molecular features are largely reflected in and summarized by the gene's expression level and expression variation. Code is available at https://github.com/BrentLab/TFPertRespExplainer.
| S-EPMC9339286 | biostudies-literature
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: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:Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MALFD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analyzed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n=3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells (KC) and monocyte-derived macrophages (MdM). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocytes/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis we demonstrate recruitment of MdMs precedes KC loss and liver damage and that MdMs may serve a role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans and this occurs prior to changes in KC number. MdMs appear to have a role in lipid uptake during early stages of MALFD.
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Project description:Background Metabolic associated fatty liver disease (MAFLD) was recently proposed to replace non-alcoholic fatty liver disease (NAFLD), which is defined as ectopic fat deposition in the liver. Hepatic steatosis is an independent predictor for insulin resistance and cardiovascular risk and hence mortality. The aim of present study was to investigate the urine molecular pattern and potential urine biomarker to distinguish healthy control, mild and severe hepatic steatosis in MAFLD patients using proteomic data. Method Hepatic steatosis was measured by Magnetic resonance imaging (MRI) that measure the proton density fat fraction (MRI-PDFF). Proteomic measurements of urine samples were done by mass spectrometry. Linear regression analyses were used to detect significant associations between the biomarkers and clinical parameters. Western blot and Elisa were performed for validation. Results Multiple pathways have been compromised in MAFLD, including the carbohydrate derivative catabolic process, glycosaminoglycan process, aminoglycan metabolic process, inflammatory response, insulin-like growth factor receptor and GTPase complex. Alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin were finally identified to be potential urine biomarkers to detect mild/severe hepatic steatosis.
2022-08-12 | PXD026333 | Pride