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Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

ABSTRACT: Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

PROVIDER: PRJNA734596 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14712129_1.fastq.gz	Fastqsanger.gz
	SRR14712129_2.fastq.gz	Fastqsanger.gz
	SRR14712130_1.fastq.gz	Fastqsanger.gz
	SRR14712130_2.fastq.gz	Fastqsanger.gz
	SRR14712131_1.fastq.gz	Fastqsanger.gz

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Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

Project description:Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN-deficient (LEPTIN-/-) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity. The LEPTIN-/- pigs showed increased body fat and significant insulin resistance by 12 months of age. To resemble non-alcoholic fatty liver disease (NAFLD) patients, LEPTIN-/- pig developed the phenotypic features of fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with age. Meanwhile, LEPTIN absence reduced phosphorylation of JAK2-STAT3 and AMPK. The alteration of JAK2-STAT3 enhanced fatty acid β-oxidation, whereas inactivation of AMPK led to mitochondrial autophagy, and both contributed to increased oxidative stress in hepatocytes. Although Leptin deletion in the rat liver altered JAK2-STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis in contrast with the LEPTIN-/- pig. To our knowledge, the LEPTIN-/- pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis. The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.

2023-09-20 | GSE176023 | GEO

Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis.

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic hepatic disease and results in non-alcoholic steatohepatitis (NASH), which progresses to fibrosis and cirrhosis. Although the Leptin deficient rodent models are widely used in study of metabolic syndrome and obesity, they fail to develop liver injuries as in patients.MethodsDue to the high similarity with humans, we generated Leptin-deficient (Leptin-/-) pigs to investigate the mechanisms and clinical trials of obesity and NAFLD caused by Leptin.ResultsThe Leptin-/- pigs showed increased body fat and significant insulin resistance at the age of 12 months. Moreover, Leptin-/- pig developed fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis with age. Absence of Leptin in pig reduced the phosphorylation of JAK2-STAT3 and AMPK. The inactivation of JAK2-STAT3 and AMPK enhanced fatty acid β-oxidation and leaded to mitochondrial autophagy respectively, and both contributed to increased oxidative stress in liver cells. In contrast with Leptin-/- pig, although Leptin deletion in rat liver inhibited JAK2-STAT3 phosphorylation, the activation of AMPK pathway might prevent liver injury. Therefore, β-oxidation, mitochondrial autophagy and hepatic fibrosis did not occurred in Leptin-/- rat livers.ConclusionsThe Leptin-deficient pigs presents an ideal model to illustrate the full spectrum of human NAFLD. The activity of AMPK signaling pathway suggests a potential target to develop new strategy for the diagnosis and treatment of NAFLD.

| S-EPMC10498639 | biostudies-literature

Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice

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

Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action

Project description:Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action

| PRJNA682376 | ENA

Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action

Project description:We employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons.

2020-12-03 | GSE162603 | GEO

Leptin-deficient Mouse Liver TMT-label Discovery Proteomics Profiling

Project description:The aim of this project was to profile the proteome of mouse-derived liver in order to identify those that showed significant quantitative different proteins among leptin-deficient (db/db) mouse, the genetic non-alcoholic fatty liver disease (NAFLD) mouse model and their lean BKS mouse group.

2022-10-14 | PXD027938 | Pride

Leptin-deficient Mouse Serum TMT-label Discovery Proteomics Profiling

Project description:The aim of this project was to profile the proteome of mouse-derived serum in order to identify those that showed significant quantitative different proteins among leptin-deficient (db/db) mouse, the genetic non-alcoholic fatty liver disease (NAFLD) mouse model and their lean bks mouse group.

2022-10-14 | PXD027937 | Pride

Genetic AMPK activation in liver protects against diet-induced obesity and NAFLD

Project description:Genetic AMPK activation in liver protects against diet-induced obesity and NAFLD

| PRJNA506251 | ENA

Genetic AMPK activation in liver protects against diet-induced obesity and NAFLD

Project description:We developed a GEMM in which AMPK can be inducibly activated in vivo (iAMPK mice). We provide here the data (RNA seq) on the transcriptional changes induced by AMPK activation in livers from mice fed a high-fat diet.

2019-02-05 | GSE122767 | GEO

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

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