Rab30 regulates lipid homeostasis in the hepatocyte during fasting
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ABSTRACT:
PROVIDER: PRJNA1003498 | ENA |
REPOSITORIES: ENA
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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.
2023-09-12 | PXD044528 | Pride
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
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
2023-09-12 | GSE240396 | GEO
Project description:In cell models, changes in the “accessible” pool of plasma membrane (PM) cholesterol are linked with the regulation of ER sterol synthesis and metabolism by the Aster family of nonvesicular transporters. However, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in liver: fasting and reverse cholesterol transport (RCT). During fasting, adipose tissue–derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester (CE) formation, cholesterol movement into bile, and VLDL production. During RCT, HDL delivers excess cholesterol to the hepatocyte PM through SR-BI. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels, and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.
2022-10-24 | GSE206278 | GEO
Project description:We tested they hypothesis that hepatocyte NAMPT mediates transcriptomic changes induced by fasting
2021-09-21 | GSE184395 | GEO
Project description:Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary change influences liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF- induced hepatocyte proliferation is driven by the combined action of intestinally produced, systemic endocrine FGF15 and localized WNT signaling. IF proliferation re-establishes a constant liver-to-body-mass ratio during periods of fasting and re-feeding, a process termed the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation, and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.
2022-08-01 | ST002263 | MetabolomicsWorkbench
Project description:Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
2022-11-15 | GSE217982 | GEO
Project description:Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
2022-11-15 | GSE217937 | GEO
Project description:The Wnt pathway, which controls crucial steps of the development and differentiation programs, has been proposed to influence lipid storage and homeostasis. In this paper, using an unbiased strategy based on high content genome-wide RNAi screens that monitored lipid distribution and amounts, we find that Wnt3a regulates cellular cholesterol. We show that Wnt3a stimulates the production of lipid droplets, and that this stimulation strictly depends on endocytosed, LDL-derived cholesterol and on functional early and late endosomes. We also show that Wnt signaling itself controls cholesterol endocytosis and flux along the endosomal pathway, which in turn modulates cellular lipid homeostasis. These results underscore the importance of endosome functions for LD formation and reveal a previously unknown cellular program controlling lipid storage and endosome transport under the control of Wnt signaling.
2015-06-20 | E-MTAB-2872 | biostudies-arrayexpress
Project description:Hepatocyte-Specific Transcriptional Profiling of the Hepatic Fasting Response
| PRJNA753936 | ENA