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Rab30 regulates lipid homeostasis in the hepatocyte during fasting

ABSTRACT: In order to facilitate inter-tissue communication and exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Rab30, a putative Golgi-localized Rab GTPase, is induced in the mouse liver by fasting and its expression is further amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) that lack the ability to oxidize fatty acids in a Pparα-dependent manner. Live-cell super-resolution imaging and biochemical in vivo proximity labeling demonstrated that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30;Cpt2 liver-specific double knockout (DKO) mice are viable and display intact Golgi ultrastructure. However, the loss of Rab30 in Rab30;Cpt2 DKO mice suppresses serum dyslipidemia observed in Cpt2L-/- single knockout mice. Corresponding with decreased serum triglyceride and cholesterol levels, Rab30;Cpt2 DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels particularly during times of excessive lipid burden

ORGANISM(S): Mus musculus

PROVIDER: GSE240396 | GEO | 2023/09/12

REPOSITORIES: GEO

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Rab30 regulates lipid homeostasis in the hepatocyte during fasting

Project description:In order to facilitate inter-tissue communication and exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Rab30, a putative Golgi-localized Rab GTPase, is induced in the mouse liver by fasting and its expression is further amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) that lack the ability to oxidize fatty acids in a Pparα-dependent manner. Live-cell super-resolution imaging and biochemical in vivo proximity labeling demonstrated that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30;Cpt2 liver-specific double knockout (DKO) mice are viable and display intact Golgi ultrastructure. However, the loss of Rab30 in Rab30;Cpt2 DKO mice suppresses serum dyslipidemia observed in Cpt2L-/- single knockout mice. Corresponding with decreased serum triglyceride and cholesterol levels, Rab30;Cpt2 DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels particularly during times of excessive lipid burden.

2024-05-04 | PXD050376 | Pride

Rab30 regulates lipid homeostasis in the hepatocyte during fasting

2023-09-12 | PXD044528 | Pride

Ppara and fatty acid oxidation coordinate hepatic transcriptional architecture (ATAC-Seq)

Project description:Mice harboring a liver-specific carnitine palmityltransferase 2 (Cpt2) knockout exhibit drastic lipid accumulation following a 24hr fast. Crossing Cpt2L-/- mice with Pparα-/- mice provides a model to drive ligand-activated Pparα signaling in liver. We use this to investigate unique patterns of Pparα target gene transcription and demonstrate the requirement for ligand-activated Pparα in maintaining transcriptionally permissive genomic architecture in liver, including regulation of promoters and enhancer elements during periods of nutrient deprivation.

2021-06-29 | GSE179050 | GEO

Ppara and fatty acid oxidation coordinate hepatic transcriptional architecture (ChIP-Seq)

Project description:Mice harboring a liver-specific carnitine palmityltransferase 2 (Cpt2) knockout exhibit drastic lipid accumulation following a 24hr fast. Crossing Cpt2L-/- mice with Pparα-/- mice provides a model to drive ligand-activated Pparα signaling in liver. We use this to investigate unique patterns of Pparα target gene transcription and demonstrate the requirement for ligand-activated Pparα in maintaining transcriptionally permissive genomic architecture in liver including regulation of promoters and enhancer elements during periods of acute nutrient deprivation.

2021-06-29 | GSE179052 | GEO

Effect of deletion of Carnitine Palmitoyltransferase2 in hepatocytes on liver gene expression upon a 24 hour fast

Project description:The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid Î²-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L-/-), an obligate step in mitochondrial long-chain fatty acid Î²-oxidation. Surprisingly, Cpt2L-/- mice survived the perinatal period and a 24hr fast with sufficient blood glucose. The loss of hepatic fatty acid oxidation resulted in a significant loss in circulating ketones that remained unaltered by fasting. Fasting induced serum dyslipidemia, hepatic steatosis and adaptations in hepatic and systemic oxidative gene expression in Cpt2L-/- mice to maintain systemic energy homeostasis. Alternatively, feeding a ketogenic diet resulted in severe hepatomegaly, liver damage and death within one week with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting. In this dataset, we include the expression data obtained from dissected mouse liver from mice fasted for 24 hours with and without the deletion of carnitine palmitoyltransferase 2 (i.e. hepatocytes unable to beta-oxidize long chain fatty acids in mitochondria). WildType and KnockOut mice were fasted for 24 hours. Three biologic replicates were compared per class, thus six mice.

2016-06-16 | E-GEOD-76079 | biostudies-arrayexpress

Effect of deletion of Carnitine Palmitoyltransferase2 in hepatocytes on liver gene expression upon a 24 hour fast

Project description:The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L-/-), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Surprisingly, Cpt2L-/- mice survived the perinatal period and a 24hr fast with sufficient blood glucose. The loss of hepatic fatty acid oxidation resulted in a significant loss in circulating ketones that remained unaltered by fasting. Fasting induced serum dyslipidemia, hepatic steatosis and adaptations in hepatic and systemic oxidative gene expression in Cpt2L-/- mice to maintain systemic energy homeostasis. Alternatively, feeding a ketogenic diet resulted in severe hepatomegaly, liver damage and death within one week with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting. In this dataset, we include the expression data obtained from dissected mouse liver from mice fasted for 24 hours with and without the deletion of carnitine palmitoyltransferase 2 (i.e. hepatocytes unable to beta-oxidize long chain fatty acids in mitochondria).

2016-06-16 | GSE76079 | GEO

Comparative proteomic identification of Rab GTPase interactors in Arabidopsis

Project description:Rab GTPases are key spatio-temporal regulators of endomembrane trafficking and endomembrane compartment identity across eukaryotes. This therefore makes them ideal targets for study of endomembrane compartment and trafficking pathway composition. In plants, few definitive interactors of Rab GTPases and cargoes of their associated trafficking pathways are known, hindering our understanding of how plants may accomplish and support some unique aspects and requirements of their post-Golgi trafficking systems. The purpose of this work was to identify candidate interactors of different post-Golgi Rab GTPases in Arabidopsis. Co-IPs were performed against tagged-versions of three different post-Golgi Rab GTPases: RAB-A5c, RAB-A2a and RAB-G3f, as well as against control wild-type (Col-0) plants. Comparative ranking of the different proteomes produced candidate interactor lists enriched in possible specific interactors of each Rab GTPase, as well as generic shared interactors. This dataset forms the basis of the characterisation work of several upcoming publications.

2023-09-21 | PXD044263 | Pride

Impaired VLDL secretion following Mttp deletion promotes tumorigenesis and is accelerated by Fabp1 deletion

Project description:Genetic polymorphisms that impair VLDL secretion are linked to hepatic steatosis, fibrosis and hepatocellular cancer (HCC). Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO mice with germline Fabp1 deletion (Fabp1/Mttp DKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKO mice on HCC incidence and progression in comparison to Fabp1/Mttp DKO mice. DEN treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared to flox controls, while diethylnitrosamine (DEN)- treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNAseq analysis performed on liver tissue at 6 months revealed mRNA changes suggesting altered monocarboxylic acid utilization and increased aerobic glycolysis, while hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to utilize glucose and glutamine. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy utilization.

2024-02-12 | GSE253701 | GEO

Loss of GPHR in the brain

Project description:The Golgi apparatus plays a central role in the protein glycosylation where it is required for secretory trafficking. Abnormal morphology of the Golgi apparatus has been widely observed in neurodegenerative disease. Golgi pH regulator (GPHR) is an anion channel essential for acidification of the Golgi lumen and its essential for normal morphology and function of the Golgi apparatus. To address the Golgi dysfunction in neuronal cells, we established brain-specific GPHR knockout mice (GPHRf/f;Nes).

2022-08-31 | GSE208622 | GEO

Expression data from ADORA1 knockout and ADORA1 APOE double-knockout mice

Project description:The goal of this study is to determine whether A1 adenosine receptor (ADORA1) plays a role in atherosclerosis development and its possible mechanisms. This dataset compares gene expression (aortas) of ADORA1 knockout mice to ADORA1+APOE double-knockout mice. Mice deficient in both ADORA1 and APOE (DKO) demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared to (APOE-KO) of the same age. Treating APOE-KO with the ADORA1 antagonist DPCPX also achieved concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO, however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also were heavier than APOE-KO. Plasma cytokine levels (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen (PCNA) expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesions and cholesterol loading and effusion [export] from bone-marrow-derived macrophages from DKO were not different from APOE-KO.

2015-06-02 | GSE39888 | GEO

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