Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice

ABSTRACT: Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

ORGANISM(S): Mus musculus

PROVIDER: GSE139015 | GEO | 2020/07/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Effect of depletion of S100A16 on gene expression during lipid accumulation of primary hepatocytes

Project description:Alcoholic liver disease (ALD) encompasses conditions ranging from simple steatosis to cirrhosis and even liver cancer. It has gained significant global attention in recent years. Despite this, effective pharmacological treatments for ALD remain elusive, and the core mechanisms underlying the disease are not yet fully comprehended. S100A16, a newly identified calcium-binding protein, is linked to lipid metabolism. Our research has discovered elevated levels of the S100A16 protein in both serum and liver tissue of ALD patients. A similar surge in hepatic S100A16 expression was noted in a Gao-binge alcohol feeding mouse model. S100a16 knockdown alleviated ethanol-induced liver injury, steatosis and inflammation. Conversely, S100a16 transgenic mice showed aggravating phenomenon. Mechanistically, we identify mesencephalic astrocyte-derived neurotrophic factor (MANF) as a regulated entity downstream of S100a16 deletion. MANF inhibited ER-stress signal transduction induced by alcohol stimulation. Meanwhile, MANF silencing suppressed the inhibition effect of S100a16 knockout on ethanol-induced lipid droplets accumulation in primary hepatocytes. Our data suggested that S100a16 deletion protects mice against alcoholic liver lipid accumulation and inflammation dependent on upregulating MANF and inhibiting ER stress. This offers a potential therapeutic avenue for ALD treatment.

2023-09-26 | GSE243683 | GEO

Hepatocyte Deletion of Triglyceride-Synthesis Enzyme DGAT2 Reduces Steatosis without Increasing Inflammation or Fibrosis

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and reprepresents a huge public health problem owing to its propensity to progress to non-alcoholic steatohepatitis (NASH), fibrosis, and liver failure. The lipids stored in hepatic steatosis are primarily triglycerides (TGs) synthesized by two acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, with DGAT2 being linked to storage of fatty acids from de novo lipogenesis, a process that is increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and the progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specfici Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction of steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduced diet-induced hepatic steatosis and supports the development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.

2020-05-26 | PXD013423 | Pride

Removing a Double Bond from Ceramides Ameliorates Insulin Resistance and Hepatic Steatosis

Project description:Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals, or tissue-specific deletion in the liver, and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed new ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and cardiometabolic disorders.

2020-01-30 | GSE132056 | GEO

Proteomics identifies organelle specific phosphorylation and reveals major subcellular reorganization in the progression of NAFLD

Project description:Obesity induced non-alcoholic fatty liver disease (NAFLD) is associated with the development of type 2 diabetes and constitutes a major health problem. A hallmark of the diseases is extensive lipid droplet (LD) formation and accumulation of toxic lipid species interfering with cellular signaling and functions. However, the cellular mechanisms during disease progression and cellular lipid overflow are poorly understood. Here, we develop a novel workflow for label free mass spectrometry based protein and phosphopeptide correlation profiling to systematically monitor the level and cellular distribution of ~6000 liver proteins and ~16,000 phosphosites during the development of dietary induced steatosis in mice. We see a redistribution of the secretory apparatus including a mislocalization of the COPI complex, and targeting of all analyzed Golgi apparatus proteins to LDs what leads to a general reduction of hepatic protein secretion. Further, we identify targeting of several organelle contact site proteins to LDs, accompanied by increased contacts between LDs and other organelles. Our resource provides the first systematic in vivo analysis of subcellular re-arrangements and organelle specific phosphorylation during disease development.

2018-10-29 | PXD007653 | Pride

Targeting phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 to treat nonalcoholic steatohepatitis

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

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice

Project description:Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice

| PRJNA578093 | ENA

Urine proteome in patients with metabolic associated fatty liver disease

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

Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice

Project description:Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2−/−/GluR-BR/R mice (ADAR2 KO) mice were fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibited protection against HFD–induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice displayed reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigated excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibited hepatic gluconeogenesis via the AMPK/CREB pathway and promoted glycogen synthesis by activating the AMPK/GSK3β pathway. These results provided novel evidence that ADAR2 KO protected against NAFLD progression through activation of AMPK signaling pathways.

2024-03-14 | GSE261185 | GEO

GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

Project description:A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

2020-07-11 | GSE154217 | GEO

Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels

Project description:Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid storage exceeds intracellular needs and induces lipotoxic events ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/ADRP) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol storage, marginally increased FA oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase of OXPHOS protein content. Diacylglycerol levels were unchanged, while ceramide levels were increased. Despite the increased intramyocellular lipid accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs towards triacylglycerol storage in LDs thereby blunting lipotoxicity-associated insulin resistance. C2C12 cells (mouse myoblast cell line) were treated with fatty acids and effects of knockdown of Perilipin 2 by siRNA were studied by gene expression profiling.

2012-06-08 | E-GEOD-38590 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data