Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE261185 | GEO | 2024/03/14
REPOSITORIES: GEO
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Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
2014-06-13 | E-GEOD-45319 | biostudies-arrayexpress
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:Purpose: While various functions of peripheral serotonin are known, the direct role of serotonin in regulating hepatic lipid metabolism in vivo is not well understood. We studied whether serotonin directly acts on liver to regulate lipid metabolism. Methods: Methods: 12 weeks aged liver-specific Htr2a KO (Albumin-Cre+/-; Htr2aflox/flox, herein named Htr2a LKO) mice and wildtype (WT) littermates were fed a high-fat diet (HFD, 60% fat calories) for 8 weeks. Results: Hepatic lipid droplet accumulation, NAFLD activity score, and hepatic triglyceride levels were dramatically reduced in HFD-fed Htr2a LKO mice compared to WT littermates. Conclusions: Gut-derived serotonin is a direct regulator of hepatic lipid metabolism via a gut TPH1-liver HTR2A endocrine axis. And shows promise as a novel drug target to ameliorate NAFLD with minimal systemic metabolic effects.
2018-11-27 | GSE120662 | GEO
Project description:Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) and exercise synergistically ameliorates NAFLD in male mice. Mechanistically, Cdo1 facilitates the binding between AMPK and kinase active Camkk2, which activates AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD
2023-08-07 | GSE239729 | GEO
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi
2014-06-13 | GSE45319 | 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:To identify molecular mechanism underlying the protection from diet-induced hepatic steatosis in AHNAK deficiency mice, we examined microarray analysis with liver sample from HFD-fed AHNAK KO and WT mice. Two-condition experiment, regular chow (CD) -fed WT vs. CD-fed AHNAK KO and High fat diet(HFD)-fed WT vs. HFD-fed AHNAK KO mice. Biological replicates: 3 control, One replicate per array.
2015-06-23 | E-GEOD-70119 | biostudies-arrayexpress
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: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:Adenosine deaminases (ADARs) are RNA binding proteins that bind to double stranded RNA and convert adenosine to inosine. Editing creates multiple isoforms of neurotransmitter receptors, including AMPA-subtype Glutamate channels such as Gria2 that is edited to introduce a Q to R amino acid change. Adar2 knock out mice die of seizures shortly after birth, but if the Gria2 Q/R editing site is mutated to mimic the edited version then the animals are viable. We performed RNA-Seq on the frontal cortices of Adar2-/- Gria2R/R mice and their Adar2+/+ Gria2R/R littermates, quantifying overall gene expression, splicing, and A to I editing in a transcriptome-wide fashion. We found 56 editing sites whose level of editing was significantly diminished in the Adar2 deficient animals. The majority of Adar2 responsive editing sites were in the coding regions of genes. Interestingly, other than Adar2 expression, there were only two additional statistically significant differentially expressed genes, Flnb and Cdh13. There were also only three exons that showed statistically significant differences in expression levels between the two genotypes. This work illustrates that ADAR2 is important in site-specific changes of protein coding sequences but has only modest effects on gene expression or splicing in vivo. 6 ADAR2 Knock out frontal cortices and 6 litter mate control frontal cortices from male mice
2016-07-03 | E-GEOD-70588 | biostudies-arrayexpress