Effect of deficiency of NLRP6 on hepatic lipids accumulation during non-alcoholic fatty liver disease in mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE239747 | GEO | 2024/01/31
REPOSITORIES: GEO
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Project description:Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, non-alcoholic fatty liver disease (NAFLD) is gaining importance. As the disease progresses it can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but the molecular mechanisms responsible for disease development remained unresolved. Here, we uncover a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway in primary hepatocytes from a preclinical model fed with a Western diet (WD). Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveals a patient-specific variability in basal MET phosphorylation, which correlates with the outcome of patients after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
2024-01-16 | MODEL2306280002 | BioModels
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (gene=LIPA, protein=LAL), which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet (FPC) would prevent the development of NAFLD. As expected, mice fed the FPC diet exhibited numerous markers of NAFLD including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the FPC diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD suggesting that targeting LAL expression is not a viable route to treat NAFLD.
2021-11-03 | GSE180377 | 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:Human genetic studies have identified several MARC1 variants as protective against non-alcoholic fatty liver diseases (NAFLD). The MARC1 variants are associated with reduced lipid profiles, liver enzymes, and liver-related mortality. However, the role of mitochondrial amidoxime reducing component 1 (mARC1), encoded by MARC1, in NAFLD is still unknown and the therapeutic potential of this target has never been developed. Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine conjugated mouse mARC1 siRNA to address this. In ob/ob mice, knockdown of mARC1 in mouse hepatocytes resulted in decreased liver weight, serum lipid enzymes, low-density lipoprotein cholesterol, and liver triglycerides. Loss of mARC1 also improved the lipid profiles and attenuated liver pathological changes in two diet-induced nonalcoholic steatohepatitis (NASH) mouse models. A comprehensive analysis of mARC1-deficient liver in NASH by metabolomics, proteomics, and lipidomics showed that mARC1 knockdown partially restored metabolites and lipids altered by diets. Taken together, loss of mARC1 protects mouse liver from NASH, suggesting a potential therapeutic approach of NASH by downregulation of mARC1 in hepatocytes.
2023-04-28 | MSV000091820 | MassIVE
Project description:We found that global heterozygous midnolin knockout attenuated the severity of nonalnonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose. This attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.
2023-05-03 | GSE226810 | GEO
Project description:17β-hydroxysteroid dehydrogenase-13 (17β-HSD13) is a liver-rich lipid droplet associated protein, encoding by gene HSD17B13, that acted as an important regulator of hepatic lipid metabolism. Increased expression of 17β-HSD13 promotes hepatic lipid accumulation in rodents, and a common loss-of-function variant of HSD17B13 (rs72613567: TA) is related to better outcome in patients with various chronic liver diseases. To understand the role of 17β-HSD13 in liver lipid metabolism under normal and high-fat feeding conditions, we characterized the effect of protein phosphorylation of 17β-HSD13 on hepatic lipid homeostasis. We identify Ser33 as an important protein kinase A (PKA)-mediated phosphorylation site of 17β-HSD13 that physically interact with ATGL and facilitates its translocation to lipid droplets to enhance lipolysis. Mutation of Ser33 to Ala (S33A) in 17β-HSD13 reduces ATGL-dependent lipolysis and increases lipid droplet size in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Consistently, a transgenic knock-in mouse strain carrying HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops liver steatosis with reduced lipolysis. Moreover, HSD17B1333A/A mice are more prone to high fat-induced hepatic steatosis and inflammation. Finally, we found Reproterol, a potential HSD17B13 modulator and FDA-approved drug, confers a protection against liver steatosis possibly through phosphorylation of 17β-HSD13 at Ser33 in a PKA-dependent manner. In summary, we demonstrate a critical role and the underlying mechanism of hepatic 17β-HSD13 phosphorylation in the pathogenesis of NAFLD. Our findings highlight the potential of targeting 17β-HSD13 phosphorylation as a novel therapeutic approach for NAFLD.
2023-03-11 | PXD037262 | Pride
Project description:Liver regeneration is an well orchestrated compensatory process that regulated by multiple factors. We recently reported the importance of chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration, however, it’s molecular mechanism is not yet understood. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Wild-type (WT) and HMGB2-knockout (KO) mice were 70% partial hepatectomized (PHx), and liver tissues were analyzed by microarray, immunohistochemistry, qPCR and western blotting. In vivo experimental findings were confirmed by in vitro experiments using HMGB2 gene knockdown in combination with de novo lipogenesis model. In WT mouse, HMGB2-positive hepatocytes were co-localized with cell proliferation markers, whereas, hepatocyte proliferation was significantly decreased in HMGB2-KO mice. Oil red-O staining detected the transient accumulation of lipid droplets at 12-24 h in WT mouse livers, however, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was prolonged until 36 h. Microarray, immunohistochemistry and qPCR results were demonstrated that lipid metabolism related genes were significantly decreased in HMGB2-KO mouse livers. In vitro experiments demonstrated that decreased lipid droplets in HMGB2-knockdown cells correlated with decreased cell proliferation activity. HMGB2 is involved in the regulation of liver regeneration through transient accumulation of lipid droplets in hepatocytes.
2023-10-14 | GSE244551 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a major public health burden and it covers a spectrum of diseases. NAFLD starts with the accumulation of lipid droplets (LDs) within hepatocytes (steatosis). Part of the challenge of studying the mechanistic processes involved in LD accumulation and their implications on the pathogenesis of human NAFLD is due to the available models. Investigating hepatic LDs in humans is challenging and relies on liver biopsies, meaning only cross-sectional data be obtained. On the other hand, LD patterns in in vitro models are poorly defined and rarely reported. Diacylgylcerol acyltransferase (DGAT)2 is one of two enzymes that carry out the final committed step in triacylglycerol (TAG) synthesis. It is unclear whether the enzymes are able to compensate for each other or whether they have distinct roles. It has been hypothesised that DGAT1 primarily utilises exogenous fatty acids and DGAT2 uses de novo-derived fatty acids. Given the important role of this enzyme in TAG synthesis and accumulation, the aims of this study are first to create a cellular model of intrahepatocellular TAG accumulation by manipulating nutritional substrates and to investigate intracellular metabolism in wildtype and DGAT2 knockout cells under these conditions. The experimental workflow for this study is as follows: Huh7 cells (either wild type or knockout) were grown in media containing 11 mM glucose and 2% human serum (HS) for seven days before additional sugars and fatty acids (FAs) were added for a further seven days. All treatments contained 11 mM glucose and 2% HS, either with 200 µM FAs (low fat low sugar; LFLS), 5.5 mM fructose + 200 µM FAs (low fat high sugar; LFHS) or 5.5 mM fructose + 800 µM FAs (high fat high sugar; HFHS). FA metabolism, lipid droplet characteristics and transcriptomic signatures were investigated.
2020-08-21 | E-MTAB-7884 | biostudies-arrayexpress
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and cardiovascular diseases, and characterized by excessive accumulation of triglycerides in the form of lipid droplets. Liver injury in NAFLD through inflammation and oxidative stress ultimately leads to development of nonalcoholic steatohepatitis and liver cancer. Recently it has been reported that catalase, a major peroxisomal antioxidant, plays a protective role in high-fat diet-induced liver injury. In this study, we further investigated the role of catalase in development of liver disease using transcriptome analysis. Catalase knockout and wild type mice were fed either normal chow or high-fat diet and the gene expression profiles in the liver were compared.
2017-12-18 | GSE108169 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD), defined as fatty infiltration in >5% of hepatocytes (steatosis) in the absence of excessive alcohol consumption, is emerging as a leading cause of liver disease worldwide (1). Subjects with NAFLD have an increased risk of progressing into non-alcoholic steatohepatitis (NASH) as well as developing type 2 diabetes, cardiovascular disease, and liver cancer (2-4). Thus, understanding the pathobiology of NAFLD is of high medical relevance for the efficient prevention and treatment of a range of complex metabolic diseases. In NAFLD, excess lipids accumulate within intrahepatocellular lipid droplets (LDs), which are composed of a neutral lipid core of mainly triacylglycerol (TAG) and cholesterol esters surrounded by a phospholipid monolayer that harbors specific proteins. Once thought to be only inert energy storage depots, hepatic LDs are increasingly recognized as organelles that orchestrate liver lipid partitioning but also play a critical role in protein quality control and storage, cell signaling, and viral replication (5). Notably, LDs are shown to dynamically interact with a variety of cellular organelles including the endoplasmic reticulum (ER), mitochondria, peroxisomes, and endosomes (6). Liver LD surface-associated proteins regulate the functional properties of LDs, and dietary fat content as well as liver metabolic status have been shown to dynamically influence the composition of hepatic LD proteins (7, 8). Consequently, exploring how LD-associated proteins affect hepatic metabolism is important for understanding the molecular pathophysiology of NAFLD. In the search for novel targets that regulate ectopic lipid accumulation in the context of nutritional stress and obesity, we identified serine/threonine protein kinase (STK)25, a member of the Ste20 kinase superfamily (9), as a hepatic LD-associated protein, which critically controls the development and progression of NAFLD (10-15). We found that STK25 knockdown attenuates lipid deposition in human hepatocytes and mouse liver by repressing lipid synthesis and enhancing β-oxidation and very-low-density lipoprotein (VLDL)-TAG secretion, with the reciprocal phenotype seen when STK25 protein is overexpressed (10-15). Notably, administration of hepatocyte-targeting GalNAc-conjugated Stk25 antisense oligonucleotide (ASO) in obese mice effectively ameliorates diet-induced hepatic steatosis as well as NASH features (i.e., liver inflammation, hepatocellular ballooning, and fibrosis), providing in vivo nonclinical proof-of-principle for the metabolic benefit of pharmacological STK25 inhibitors (15). Furthermore, we observed that STK25 levels in human liver biopsies correlate with the severity of NASH, and several common non-linked single nucleotide polymorphisms (SNPs) in the human STK25 gene are associated with altered liver fat content (12-14). Although these studies suggest a key role for STK25 in the control of liver LD dynamics, the mechanism-of-action of STK25 in regulation of hepatic lipid partitioning has remained elusive. To provide novel insights into biological function of STK25 in the liver under steatotic conditions, we here characterized the hepatic LD-associated phosphoproteome in Stk25 knockout mice and their wild-type littermates following high-fat diet feeding using non-biased approach by isobaric tagging for relative quantification. Of the 4,515 proteins and 982 phosphoproteins identified with a 1% false discovery rate, we report a total of 131 proteins and 69 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, antioxidant defense, and ubiquitination-mediated proteolysis were coordinately regulated in the livers from high-fat-fed Stk25-/- mice compared with wild-type controls.
2021-09-08 | PXD015311 | Pride