Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr−/−.Leiden mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE209762 | GEO | 2023/03/20
REPOSITORIES: GEO
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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:Abstract: - Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2’-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2’-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on HFD, were treated with 2’-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2’-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2’-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t=12 weeks. 2’-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by functional transcriptome analyses showing that 2’-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2’-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in ER stress. 2’-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. - In conclusion, long-term prebiotic treatment with 2’-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2’-fucosyllactose to correct dysmetabolism and insulin resistance.
2022-05-24 | GSE195862 | GEO
Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.
2010-09-09 | E-GEOD-24031 | biostudies-arrayexpress
Project description:Background & Aims: In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, the main determinant of NASH-associated mortality. The short chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remains unclear. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.
2021-12-21 | GSE179395 | GEO
Project description:Background: Non-alcoholic steatohepatitis (NASH) has become one of the most common liver diseases and is still without approved pharmacotherapy. Lifestyle interventions using exercise and diet change remain the current treatment of choice and even a small weight loss (5-7%) can already have a beneficial effect on NASH. However#the underlying molecular mechanisms of exercise and diet interventions remain largely elusive#and it is unclear whether they exert their health effects via similar or different pathways. Methods: Ldlr-/-.Leiden mice received a high fat diet (HFD) for 30 weeks to establish an advanced state of NASH/fibrosis with simultaneous atherosclerosis development. Groups of mice were then either left untreated (control group) or were treated for 20 weeks with exercise (running wheel)#diet change (switch to a low fat chow diet) or the combination thereof. The liver and distant organs including heart#white adipose tissue (WAT) and muscle were histologically examined. Comprehensive transcriptome analysis of liver#WAT and muscle revealed the organ-specific effects of exercise and diet and defined the underlying pathways. Results: Exercise and dietary change significantly reduced body weight#fat mass#adipocyte size and improved myosteatosis and muscle function with additive effects of combination treatment. WAT inflammation was significantly improved by diet change#tended to be reduced with exercise#and combination therapy had no additive effect. Hepatic steatosis and inflammation were almost fully reversed by exercise and diet change#while hepatic fibrosis tended to be improved with exercise and was significantly improved with diet change. Additive effects for the combination therapy were shown for liver steatosis and associated liver lipids#and atherosclerosis#but not for hepatic inflammation and fibrosis. Pathway analysis revealed complementary effects on metabolic pathways and lipid handling processes#thereby substantiating the added value of combined lifestyle treatment. Conclusions: Exercise#diet change and the combination thereof can reverse established NASH/fibrosis in obese Ldlr-/-.Leiden mice. In addition#the lifestyle interventions had beneficial effects on atherosclerosis#WAT inflammation and muscle function. For steatosis and other parameters related to adiposity or lipid metabolism#exercise and dietary change affected more distinct pathways that acted complementary when the interventions were combined resulting in an additive effect for the combination therapy on important endpoints including NASH and atherosclerosis. For inflammation#exercise and diet change shared several underlying pathways resulting in a net similar effect when the interventions were combined.
2021-07-10 | GSE179394 | GEO
Project description:Abstract: Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis, and improve the metabolic aspects of the disease. Putative disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased total bile acid excretion. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition, while total plasma bile acid levels remained constant. Non-alcoholic fatty liver disease activity score was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1β, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of non-alcoholic steatohepatitis pathophysiology.
2019-06-07 | GSE129306 | GEO
Project description:Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin-1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The PHB1 protein levels in adipose tissues were markedly decreased in mice fed a high-fat diet (HFD) compared to those fed a chow diet. To explore the function of adipocyte PHB1 in the progression of NAFLD, mice with adipocyte-specific (adipo) deletion of Phb1 (Phb1adipo-/- mice) were generated. Notably, Phb1adipo-/- mice did not develop obesity but displayed severe liver steatosis under HFD feeding. Compared to HFD-fed wild-type (WT) mice, HFD-fed Phb1adipo-/- mice displayed dramatically lower fat mass with significantly decreased levels of total adipose tissue inflammation, including macrophage and neutrophil number as well as the expression of inflammatory mediators. To our surprise, although liver steatosis in Phb1adipo-/- mice was much more severe, liver inflammation and fibrosis were similar to WT mice after HFD feeding. RNA sequencing analyses revealed that the interferon pathway was markedly suppressed while the bone morphogenetic protein 2 pathway was significantly up-regulated in the liver of HFD-fed Phb1adipo-/- mice compared with HFD-fed WT mice. Conclusion: HFD-fed Phb1adipo-/- mice display a subtype of the lean NAFLD phenotype with severe hepatic steatosis despite low adipose mass. This subtype of the lean NAFLD phenotype has similar inflammation and fibrosis as obese NAFLD in HFD-fed WT mice; this is partially due to reduced total adipose tissue inflammation and the hepatic interferon pathway.
2022-09-17 | GSE213355 | GEO
Project description:Abstract Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking. In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology. We show that Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed controls, indicating an altered overall microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD affected multiple molecular pathways: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent. This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.
2023-06-18 | GSE234425 | 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:Abstract: Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however it remains unclear whether individual BCAAs can attenuate already established NASH and oxidative-inflammatory stress associated with it. Therefore, mice were first put on a run-in fast food diet (FFD) for 26 weeks, these obese mice were then treated with individual BCAAs valine or isoleucine (3% of FFD) for another 12 weeks and compared to FFD controls. Valine and isoleucine treatment did not affect obesity, dyslipidemia, gut permeability or fecal fatty acid excretion, although significantly reduced hyperinsulinemia compared with FFD. Valine and isoleucine significantly reduced ALT, CK-18M30, and liver steatosis with a particularly pronounced effect on the microvesicular component (-61% by valine and -71% by isoleucine). Hepatic 4-hydroxynonenal (4-HNE) immunoreactivity, a marker for oxidative stress-induced lipid peroxidation, was also significantly decreased. Functional genomics analysis demonstrated that valine and isoleucine upregulated BCAA metabolism, deactivated master regulators of anabolic pathways related to steatosis (e.g. SREBPF1) and activated master regulators of mitochondrial biogenesis (e.g. PPARGC1a) and lipid catabolism (e.g. ACOX1, AMPK). The correction of critical metabolic pathways by valine and isoleucine was accompanied by a significant decrease of liver inflammation, and suppression of many FFD-stimulated cytokine and chemokine pathways including IL-1β, TNFα and CCR2 signaling. In conclusion, the dietary intervention with either valine or isoleucine corrected multiple metabolic processes in liver and reduced steatosis and inflammation with profound effects on oxidative stress and inflammatory pathways. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.
2022-06-30 | GSE195798 | GEO