Steatosis Drives monocyte-derived Macrophage Accumulation in Human Metabolic Dysfunction-Associated Fatty Liver Disease
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ABSTRACT:
PROVIDER: PRJNA984298 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24939759_1.fastq.gz | Fastqsanger.gz | |||
| SRR24939759_2.fastq.gz | Fastqsanger.gz | |||
| SRR24939760_1.fastq.gz | Fastqsanger.gz | |||
| SRR24939760_2.fastq.gz | Fastqsanger.gz | |||
| SRR24939761_1.fastq.gz | Fastqsanger.gz |
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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.
2023-10-01 | GSE235079 | GEO
Project description:Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors. A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.
2023-08-08 | GSE236974 | GEO
Project description:Background & aimsMetabolic 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 MAFLD 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.MethodsLiver tissue from 21 participants was collected at time of bariatric surgery and analysed 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.ResultsWe 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 and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD.ConclusionsThe 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. MdMs appear to participate in lipid uptake during early stages of MALFD.Impact and implicationsMetabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.
| S-EPMC10585307 | biostudies-literature
Project description:Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. To investigate the underlying mechanisms of hepatic dysfunction we used a rat model of malnutrition by placing weanling rats on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Low protein diet-fed rats developed hypoalbuminemia and severe hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated impaired peroxisomal function. Loss of peroxisomes was followed by accumulation of dysfunctional mitochondria and decreased hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial fatty acid β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. These findings provide important insight into the metabolic disturbances associated with malnutrition and have potentially profound clinical consequences with respect to the management of malnourished children worldwide.
2016-06-18 | GSE63096 | GEO
Project description:Metabolic dysfunction-associated fatty liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes (T2D), can progress to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. Ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms. Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.
2025-08-07 | GSE294746 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARa) transcription and fatty acid b-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARa-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappa B and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH.
2024-04-21 | MSV000094587 | MassIVE
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARα) transcription and fatty acid β-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARα-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappaB and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH.
2024-08-07 | GSE265985 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immunometabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is associated with diverse features including oxidative stress, impaired mitochondrial function andlipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and investigation into a potential drug target that has overarching effects on these features will provide benefits towards discovering effective treatments for NAFLD. Here, we examined the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in in vitro fatty liver model. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic condition, and our transcriptome analysis revealed that PON2 deficiency disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, liver fibrosis, and hepatic inflammation. PON2 promoted the activation of overall autophagy pathway, especially mitophagy cargo sequestration, which may be considered as an underlying mechanism that contributed to the role of PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide mechanistic foundation on the prospect of targeting PON2 for the development of novel therapeutics for NAFLD in the future.
2022-09-26 | GSE213653 | GEO
Project description:Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2, however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing HMGCS2 and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolism pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance. To determine the global impact of Foxa1 on human liver gene transcription, microarray expression analyses were performed in HepG2 cells transfected with Ad-Foxa1 or Ad-Control. We used microarrays to detail the global programme of gene expression in HepG2 cells infected with Ad-Foxa1 or control adenovirus (insertless Ad-pACC).
2011-07-07 | E-GEOD-30447 | biostudies-arrayexpress
Project description:Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2, however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing HMGCS2 and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolism pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance. To determine the global impact of Foxa1 on human liver gene transcription, microarray expression analyses were performed in human hepatocytes transfected with Ad-Foxa1 or Ad-Control. We used microarrays to detail the global programme of gene expression in human hepatocytes infected with Ad-Foxa1 or control adenovirus (insertless Ad-pACC).
2011-07-07 | E-GEOD-30450 | biostudies-arrayexpress