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Nonvesicular sterol transport is a metabolic immune checkpoint that guards dietary lipid uptake (scRNA-Seq)

ABSTRACT: The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular functions are not well defined. Here we show that the nonvesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated “accessible” cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and in Th17 cytokine production. Furthermore, Aster-A associates with STIM1 and negatively regulates STIM1-dependent calcium flux during activation of mouse and human T cells. Finally, mucosal Th17 response towards commensals is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells stimulates IL-22 production, which reduces intestinal fatty acid absorption, and confers resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.

ORGANISM(S): Mus musculus

PROVIDER: GSE277138 | GEO | 2025/07/20

REPOSITORIES: GEO

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Nonvesicular sterol transport is a metabolic immune checkpoint that guards dietary lipid uptake

Project description:The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular functions are not well defined. Here we show that the nonvesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated “accessible” cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and in Th17 cytokine production. Furthermore, Aster-A associates with STIM1 and negatively regulates STIM1-dependent calcium flux during activation of mouse and human T cells. Finally, mucosal Th17 response towards commensals is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells stimulates IL-22 production, which reduces intestinal fatty acid absorption, and confers resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.

2025-07-20 | GSE277067 | GEO

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

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

Cooperation between ASTER-dependent nonvesicular transport and NPC1L1 facilitates dietary cholesterol uptake

Project description:Intestinal cholesterol absorption is an important determinant of systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe, is a critical player in dietary cholesterol uptake. But how cholesterol moves within the cell downstream of NPC1L1 is unknown. Here we show that the nonvesicular sterol transporters Aster-B and -C cooperate with NPC1L1 to deliver dietary cholesterol from the gut lumen to the enterocyte ER for chylomicron packaging. Aster proteins are recruited to the enterocyte plasma membrane (PM) in response to NPC1L1-dependent cholesterol accumulation. Mice lacking Asters in intestine have impaired cholesterol absorption, and reduced plasma cholesterol. NanoSIMS imaging and tracer studies reveal delayed lipid trafficking into chylomicrons in Aster-deficient enterocytes. Interestingly, in addition to potently blocking NPC1L1, ezetimibe is also a low-affinity inhibitor of Aster-B and -C but not -A, and the structure of the Aster-C-ezetimibe complex reveals the basis for this selectivity. Our findings support a model in which NPC1L1 enriches dietary cholesterol at the apical PM, and ASTERs subsequently traffic this cholesterol to the ER. The findings identify the enterocyte Aster pathway as potential target for treatment of hypercholesterolemia. Alessandra Ferrari, PhD

2023-12-21 | GSE206780 | GEO

Calcium signaling controls pathogenic Th17 cell-mediated inflammation by regulating mitochondrial metabolism

Project description:Pathogenic Th17 cells play an important role in many autoimmune and inflammatory diseases. Their function is dependent on signaling through the T cell receptor (TCR) and cytokines that activate the transcription factor signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+) influx through the Ca2+ release-activated Ca2+ (CRAC) channel. We here show that deletion of STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and multiorgan inflammation associated with STAT3C expression. Deletion of STIM1 in pathogenic Th17 cells impairs the expression of nuclear encoded mitochondrial electron transport chain genes and oxidative phosphorylation (OXPHOS) but enhances reactive oxygen species (ROS) production. Deletion of STIM1 or inhibition of OXPHOS is associated with impaired Th17 cell function and a non-pathogenic Th17 gene expression signature. Our findings establish STIM1 and Ca2+ signals as a critical regulator of OXPHOS and oxidative stress in pathogenic Th17 cells and multiorgan inflammation.

2019-01-17 | GSE125204 | GEO

STIM1-mediated gene expression in non-pathogenic and pathogenic CD4+ Th17 cells

Project description:Immunity to fungal infections is mediated by cells of the innate and adaptive immune system. Activation of immune cells requires Ca2+ influx through the Ca2+ channel ORAI1, which is activated by stromal interaction molecule 1 (STIM1). Th17 cells are essential for immunity to C. albicans infection and require Ca2+ influx for expression of IL-17A and other Th17 cytokines. In mice, deletion of STIM1 and thus Ca2+ influx in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion in CD4 T cells had different effects on gene expression programs in pathogenic (proinflammatory) and non-pathogenic Th17 cells. STIM1 deletion in non-pathogenic Th17 cells, which are required for antifungal immunity, compromised the expression of genes in several metabolic pathways including Foxo and HIF-1a signaling as well as the TCA cycle and oxidative phosphorylation (OXPHOS). Consequently, STIM1 deficient non-pathogenic Th17 cells had impaired glycolysis and mitochondrial respiration. By contrast, STIM1 deletion in pathogenic Th17 cells showed only attenuated mitochondrial function but normal glycolysis.

2020-06-01 | GSE149162 | GEO

RNA-sequencing of liver tissue from wild type and Gramd1c knockout mice fed with high and low cholesterol diet

Project description:The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER . Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in tissue cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions.transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited.

2024-01-11 | GSE250230 | GEO

Cooperation between ASTER-dependent nonvesicular transport and NPC1L1 facilitates dietary cholesterol uptake

Project description:Cooperation between ASTER-dependent nonvesicular transport and NPC1L1 facilitates dietary cholesterol uptake

| PRJNA852178 | ENA

GRAMD1B is a novel regulator of lipid homeostasis, autophagic flux, and phosphorylated tau.

Project description:Lipid dyshomeostasis and tau pathology are found in frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology and molecular mechanisms underlying this relationship remain unclear. Using single-cell RNA-sequencing, we report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids from patient-derived induced pluripotent stem cells with the MAPT R406W mutation compared to isogenic controls. Mutant neural organoids also exhibit altered lipid species, increased phosphorylated tau, and decreased neuronal activity. Increased GRAMD1B is also found in human FTLD and AD cases and PS19 tau mice. Phosphorylated tau, free cholesterol, and lipid droplets are also increased in human FTLD and AD cases. Furthermore, GRAMD1B overexpression increases pathological tau and lipid dyshomeostasis, which may be due to blocking of autophagic flux. Our findings suggest GRAMD1B may be a new player in the regulation of autophagic flux, cholesterol transport, and tau pathology in FTLD and AD.

2025-03-17 | GSE278619 | GEO

Effects of Paramylon Extracted from Euglena gracilis EOD-1 on lipid metabolism in the Ileum and Liver in Diet-Induced Obese Mice Analyzed by DNA Microarray.

Project description:We have previously shown that paramylon (PM) supplementation to a high fat diet reduces the postprandial glucose rise, serum total and LDL-cholesterol, and abdominal fat accumulation in mice; however, the mechanism has not been determined. We evaluated the potential mechanism in male C57BL/6J mice fed a high-fat diet supplemented with 5% PM powder, extracted from Eu-glena gracilis, for 12 weeks. Abdominal fat weight, and serum lipids were measured; ileal and hepatic mRNA expression were assessed using DNA microarray and real-time PCR. The poten-tial mechanism of PM on modulating lipid metabolism was explored by gene ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Dietary supplementation with PM resulted in decreased abdominal fat accumulation and serum LDL-cholesterol concentrations via suppression of the digestion and absorption pathway in the ileum and activation of the hepatic PPAR signaling pathway. Improvement in glucose tolerance may be the result of lipid metabolism modification because the glucose metabolism pathway was not detected by GO classification and KEGG pathway analysis. PM intake also directly enhanced immunoglobulin production.

2021-08-04 | GSE181289 | GEO

STIM1 controls T cell mediated immune regulation and inflammation in chronic infection

Project description:Influence of STIM1 on the transcriptome of CD4+ T cell subsets STIM1 is critical for the regulation of the intracellular Ca2+ homeostasis in CD4+ T cell. Loss of function mutations in STIM1 in patients result in severe immuno deficiency and recurrent infections. Using conditional knock out mice for STIM1, we investigated the role of STIM1 in T cells during chronic infections by in-vivo and in-vitro experiments. We found that STIM1 is required for T cell-mediated immunity to chronic infection with Mycobacterium tuberculosis (Mtb) as STIM1-deficient mice succumb to infection faster than littermate controls, have increased mycobacterial burdens and severe pulmonary infiltration with myeloid and lymphoid cells .Using the Affymetrix Mouse Exon 1.0 platform, we analyzed the influence of STIM1 expression on the transcriptom of CD4+T cells in-vitro. We found that STIM1 is required for the regulation of apoptosis related genes after TCR stimulation as well as for the induction of a transcriptonal program that polarizes naive CD4+ T cells into inducible CD4+ T regulatory cells (iTreg). Together with our in-vivo findings, these experiments reveal that STIM1 is essential for immune regulation to prevent an injurious inflammatory response during chronic infection.

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