Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The effects of SGLT-2 inhibitors canagliflozin on hepatic transcription

ABSTRACT: We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity. Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and CV risk in T2D, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. We utilized an integrated transcriptomic-metabolomics approach to demonstrate that CANA modulates key nutrient-sensing pathways, with activation of AMPK and inhibition of mTOR, independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Taken together, these data demonstrate that SGLT-2 inhibition triggers a fasting-like transcriptional and metabolic paradigm.

ORGANISM(S): Mus musculus

PROVIDER: GSE148702 | GEO | 2020/04/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities, but not Inflammation and Injury in Mice

Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury. Total RNA obtained from liver of 4 control vs. 4 Mogat1 ASO treated higf-fat diet (HFD) fed mice.

2014-11-05 | E-GEOD-60349 | biostudies-arrayexpress

Transcription profiling of mouse liver from JNK knocked down animals

Project description:Liver-specific Knockdown of JNK1 Up-regulates Proliferator-activated Receptor Coactivator 1 and Increases Plasma Triglyceride despite Reduced Glucose and Insulin Levels in Diet-induced Obese Mice. The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor coactivator 1, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice. Experiment Overall Design: Liver sample from vehicle, GFP Adv-shRNA, or Jnk1 Adv-shRNA treated DIO mice with 5, 4, and 5 replicates, respectively

2008-06-15 | E-GEOD-7648 | biostudies-arrayexpress

Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities, but not Inflammation and Injury in Mice

2014-11-05 | GSE60349 | GEO

Liver-specific knockdown of JNK1

2007-10-02 | GSE7648 | GEO

Canagliflozin regulates ferroptosis to ameliorate heart failure in rats with preserved ejection fraction

Project description:Chronic heart failure (CHF), with whether reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), is the end-stage of various cardiovascular diseases and severely affects the patients’ lifespan. There has been no effective drugs to improve clinical outcomes for a long time. Sine the recent years, as a hypoglycemic drug, sodium-glucose cotransporter 2 inhibitor (SGLT2i) has aroused great attention due to it’s cardiovascular benefits. However, the underlying mechanisms remain unclear, particularly regarding ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death in heart failure (HF). Here, we discovered and demonstrated that ferroptosis was a key mechanism in rat model of high-salt diet-induced HF, characterized by iron overloading and lipid peroxidation, which was blocked by canagliflozin administration. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for HF prevention and canagliflozin might display cardiovascular benefits through ferroptosis mitigation.

2022-05-20 | PXD029031 | Pride

Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

Project description:Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. We show that FXR isoforms have specific effects on hepatic metabolism and uncover novel pathways under their control. Gene expression profiling of hepatocytes expressing each FXR variant revealed large differences in their target gene sets. Notably, FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves insulin sensitivity. FXRα2 expression in Fxr-/- mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Thus, pharmacological or lifestyle interventions, such as exercise, aimed at modulating hepatic FXR splicing may improve the therapeutic efficacy of FXR agonists.

2015-09-28 | GSE73035 | GEO

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

Project description: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.

2020-07-08 | GSE139015 | GEO

mouse gut metagenome

Project description:Canagliflozin reduces plasma uremic toxins with alterations of the intestinal microbiota in CKD mice

| PRJDB6439 | ENA

The effects of SGLT-2 inhibitors canagliflozin on hepatic transcription

Project description:We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity.

2021-05-13 | GSE114614 | GEO

Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance

Project description:Insulin resistance not compensated by secretion reduces energy storage, but little is known about its effect upon energy expenditure (EE). Insulin receptor substrates Irs1 and Irs2 mediate signaling in all tissues, resulting in the inhibition of FoxO transcription factors. We found that hepatic disruption of Irs1 and Irs2 (LDKO mice) attenuated high-fat diet (HFD)-induced obesity and increased whole-body EE in a FoxO1-dependent manner. Hepatic disruption of Fst (follistatin), a FoxO1-regulated hepatokine, normalized EE in LDKO mice and restored adipose mass during HFD consumption. Moreover, hepatic Fst disruption alone increased fat mass accumulation, whereas hepatic overexpression of Fst attenuated high HFD-induced obesity. Excess circulating Fst in overexpressing mice neutralized Mstn (myostatin), activating mTORC1-promoted pathways of nutrient uptake and EE in skeletal muscle. Similar to Fst overexpression, direct activation of muscle mTORC1 also reduced adipose mass. We conclude that Fst-promoted EE in muscle attenuates obesity during hepatic insulin resistance.

2024-02-29 | GSE260531 | GEO

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