Serotonin signals through a gut-liver axis to regulate hepatic steatosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE120662 | GEO | 2018/11/27
REPOSITORIES: GEO
Similar Datasets
Project description:Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step in the development of NAFLD. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism to NAFLD and systemic metabolic homeostasis. We show that LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress and damage in response to high fat diets. Furthermore, increased energy expenditure accompanied by enhanced adipose tissue browning was observed in LKO mice. Mechanistically, hepatic CPT1A deficiency actives the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis and the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Thus, our study demonstrates that liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
2022-09-10 | GSE183650 | GEO
Project description:Matrin-3 is an RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor. Matrin-3 expression was induced in the steatotic livers of mice and humans. Liver-specific matrin-3 knockout (LKO) exacerbated high-fat diet (HFD)-induced steatosis, acute phase response, and inflammation in the liver of mice. Bulk RNA-seq and bioinformatics analysis identified 1,333 and 239 differentially expressed genes (fold change > 1.5 & Padj < 0.05), respectively in the livers of female and male matrin-3 LKO mice. Gene Set Enrichment Analysis revealed that the top most enriched Gene Ontology Biological Process was the “Xenobiotic metabolic process” in female matrin-3 floxed mice that is downregulated. The top two enriched biological processes are “Acute inflammatory response” and “Acute phase response” in the liver of female LKO mice that are upregulated. Several GO terms related to lipid metabolism and xenobiotic metabolism were enriched in the livers of male mice. Real-time qPCR revealed that the expression of many genes involved in xenobiotic metabolism was reduced in the liver of female LKO mice and to a lesser extent in the liver of male LKO mice, while the expression of acute-phase response genes was induced in the liver of female but not male LKO mice. Our data demonstrated that liver-specific matrin-3 deficiency re-programs the hepatic transcriptome enriched for xenobiotic metabolism pathway, acute-phase and inflammatory response signaling in the liver of HFD-fed mice.
2024-10-01 | GSE246706 | GEO
Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.
2023-03-23 | PXD040233 | Pride
Project description:Background and aims: Trichosanthis Pericarpium injection (TPI) produces a significant effect on regulating lipid metabolism and antioxidation, whose effects on non-alcoholic fatty liver disease (NAFLD) still remain unclear. In this study, we delved into the pharmacological functions of TPI on NAFLD and its underlying mechanisms. Methods: NAFLD mice model was induced by administering a high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of TPI for 4 weeks. Concurrently, to explore the potential mechanisms, we utilized AML12 cells exposed to oleic acid (OA) as an in vitro model. Non target metabolomics and transcriptomics were used to explore the mechanism by which TPI improves lipid metabolism in mouse liver. Results: Our findings indicate that TPI significantly improved metabolic abnormalities and hepatic fat deposition in HFD mice. TPI treatment also yielded analogous results in AML12 cells treated with OA. Metabolomic analysis revealed alterations in metabolites in NAFLD mice, with ABC transporters exhibiting the most prominent changes. Further screening of gene changes related to this pathway showed a significant increase in ABCC5 expression in the NAFLD mice, while TPI treatment effectively reduced the expression level of ABCC5. Transcriptomic analysis demonstrated a marked increase in the expression of the transcription factor KLF6 in the NAFLD group, which positively correlated with ABCC5 expression. Further luciferase reporter gene experiments confirmed that KLF6 can directly regulate the expression of ABCC5, thereby affecting lipid metabolism and participating in the development of NAFLD. Notably, TPI treatment was able to reverse this process. Conclusions: In conclusion, TPI improves NAFLD by alleviating hepatic lipid metabolism dysregulation through the KLF6/ABCC5 pathway.
2024-07-29 | GSE273292 | GEO
Project description:Major causes of lipid accumulation in liver are increased import, synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelle controlling energy homeostasis, i.e. mitochondria. However, peroxisomes appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non-alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes next to mitochondria in excessive hepatic lipid accumulation we used the leptin resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia induced diabetes with obesity and NAFLD. We used microarrays to determine differences in hepatic gene expression in a mouse model for NAFDL (BKS.Cg-Leprdb (db/db)) and their wildtype littermates C57BL/KSlepr+/+ (BKS) to determine the effect of persistent hepatic lipid accumulation.
2015-03-23 | GSE59930 | GEO
Project description:Obesity is tightly associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of obesity-induced fatty liver remain largely unknown.In order to identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, we performed a clustering analysis of Affymetrix arrays,which revealed that a number of mRNAs were dys-regulated in the livers of mice fed a high-fat diet (HFD), compared with mice fed a normal chow diet (ND). To identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, male C57BL/6 mice aged 8 weeks were fed a normal diet (ND) or high-fat-diet (HFD) containing 60 Kcal% of fat for 12 weeks. Then mice were sacrificed and total RNAs were isoloated from hepatic tissues. Affymetrix array hybridisation and scanning were performed using Mouse Genome 430 2.0 chips.Total RNA samples obtained from six mice per group (ND and HFD) and pooled by each of the two were used for microarray analysis.
2014-05-09 | E-GEOD-57425 | biostudies-arrayexpress
Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 ingredients: Hepar compositum (HC-24). Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis (next generation sequencing). Transcriptomics results were further substantiated with immunohistochemical and liver lipid analyses. Results: HFD feeding induced obesity and metabolic dysfunction that was associated with adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not affect total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes involved in inflammation (e.g. neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e. predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24. Conclusions: Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
2021-03-01 | GSE163652 | GEO
Project description:The ER-resident prote in fat-inducing transcript 2 (FIT2) catalyzes acyl-CoA cleavage in vitro, and in cells is required for endoplasmic reticulum (ER)homeostasis and normal lipid storage. The gene encoding FIT2 is essential for viability of mice and worms. Whether FIT2 acts as anacyl-CoA diphosphatase in vivo and how this activity affects liver, where the protein was discovered,is unknown. Here, we report that hepatocyte-specific Fitm2 knockout (FIT2-LKO) mice exhibited elevated acyl-CoA levels, ER stress, and signs of liver injury. FIT2-LKO mice had increased triglyceride (TG) content in liver when fed a chow diet, compared with control littermates due in part to impaired secretion of TG-rich lipoproteins and reduced capacity for fatty acid oxidation. Challenging FIT2-LKO mice with a high-fat diet to increase FIT2 acyl-CoA substrates worsened hepatic ER stress and liver injury, yet unexpectedly reversed the steatosis phenotype, similar to what is observed in FIT2-deficient cells loaded with fatty acids. Our findings show that FIT2 acts as anacyl-CoA diphosphatase in vivo and is crucial for normal hepatocyte function and ER homeostasis in murine liver
2023-05-10 | PXD033884 | Pride
Project description:High Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods, and its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the exact molecular mechanisms by which HFCS impacts hepatic metabolism are still unclear, especially in the context of obesity. In contrast, the vast majority of current studies in the field focus either on the detrimental role of fructose on NAFLD or compare the additive impact of fructose versus glucose in this process. Besides, studies elaborating on the role of fructose in NAFLD utilize molecular fructose, rather than HFCS, thus lacking simulation of human NAFLD in a more realistic way. Herein, by engaging combined omic approaches, we sought to characterize the additive impact of HFCS on NAFLD during obesity and recognize candidate pathways and molecules which could mediate the exaggeration of steatosis under these conditions. To achieve this goal, C57BL/6 male mice were fed a normal-fat (ND), a high-fat (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic and lipidomic analyses were conducted and utilized separately or in an integrated mode to identify HFCS-related molecular alterations of the hepatic metabolic landscape. Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed greater aggravation of hepatic steatosis. Importantly, the HFD-HFCS hepatic proteome was characterized by an upregulation of the enzymes implicated in de novo lipogenesis (DNL), while palmitic-acid containing diglycerides were significantly increased in the HFD-HFCS hepatic lipidome, as compared to the HFD group. Integrated omic analysis further suggested that TCA cycle overstimulation, is likely contributing towards the intensification of steatosis in the HFD-HFCS dietary theme. Overall, our results imply that HFCS may significantly contribute to NAFLD aggravation during obesity, with its fructose-rich properties being the main suspect.
2023-08-03 | PXD033612 | Pride
Project description:Objective：Phospholipase D1 (PLD1), a phosphatidylcholine-hydrolyzing enzyme, has been found to be involved in cellular lipid metabolism. However, how PLD1 involves in hepatocyte lipid metabolism and thus affects non-alcoholic fatty liver diseases (NAFLD) has not been explicitly explored. Method: NAFLD is induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) mice or control (Pld1-Flox) mice with a high fat diet (HFD) for 20 weeks. Plasma glucose and lipid levels, liver lipid and function parameters and inflammation- and fibrogenesis-related gene expression levels were studied. Changes in lipid composition of liver were detected by lipidomic analyses. Changes in gene expression profile were detected by mRNA sequencing. In vitro, alpha mouse liver 12 (AML12) cells were incubated with sodium palmitate (SP) to explore the mechanisms of PLD1 on development of NAFLD. The protein levels of PLD1 and CD36 were detected in the liver tissues of NAFLD patients. Finally, the therapeutic effect of NAFLD by inhibiting PLD with 5-Fluoro-2-indolyl deschlorohalopemide (FIPI) was examined. Results: PLD1 expression levels were increased in the liver tissues of NAFLD patients and the hepatocytes of HFD-induced mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited lower plasma glucose and lipids levels, and decreased lipid accumulation, inflammation and fibrosis related gene expression levels in the liver tissues after HFD feeding. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acids (PA) and lyso-PAs (LPA) levels in the liver tissues after NAFLD. Transcriptomic analysis showed that hepatocyte specific deficiency of PLD1 mainly decreased CD36 expression levels in the NAFLD liver tissues, which was confirmed at the protein and gene expression levels. In vitro, inhibition of PLD1 markedly decreased CD36 expression and lipid accumulation in SP treated AML12 cells. Furthermore, PA, the downstream product catalyzed by PLD1, increased the expression levels of CD36 and lipid accumulation in vitro, which was reversed by PPARγ antagonist. These suggested that PPARγ played an important role in transcriptional regulation of CD36 expression after PA stimulation. Finally, PLD inhibitor FIPI had significant therapeutic effect on HFD-induced NAFLD. Conclusion: Hepatocyte-specific deficiency of PLD1 ameliorates lipid accumulation and NAFLD development by inhibiting PPARγ/CD36 pathway conducted by PA.
2023-08-01 | GSE207281 | GEO