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Alterations in lysosomal gene expression and lipid homeostasis in patient-derived liver organoids with acid sphingomyelinase deficiency

ABSTRACT: We generated hepatic organoids from Nieman Pick Type B patients with the aim to investigate their lipid status. To discover genes related to lipid metabolism likely involved in lipid deposits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236213 | GEO | 2023/07/04

REPOSITORIES: GEO

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Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis.

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Alterations in lysosomal gene expression and lipid homeostasis in patient-derived liver organoids with acid sphingomyelinase deficiency

Project description:Alterations in lysosomal gene expression and lipid homeostasis in patient-derived liver organoids with acid sphingomyelinase deficiency

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Liver organoids generated from individuals carrying PiZZ variant of alpha-1-antitrypsin contain high lipid content

Project description:We generated hepatic organoids from MZ and ZZ patients with the aim to investigate their lipid status To discover genes related to lipid metabolism likely involved in lipid deposits.

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Cell Autonomous Lipid Handling Defects in Stargardt iPS Cell-Derived Retinal Pigment Epithelium Cells

Project description:Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have contributed to its lacking treatments. Here we show that ABCA4 knockout or Stargardt patient’s induced pluripotent stem cells-derived RPE (STGD1-iRPE) differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity, indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are reduced by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Overall, our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.

2022-11-16 | GSE198362 | GEO

Lipid raft composition modulates sphingomyelinase activity and ceramide-induced membrane physical alterations.

Project description: Not available

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Lysosomal targeting and trafficking of acid sphingomyelinase to lipid raft platforms in coronary endothelial cells.

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S1P lyase deficiency disrupts lipid homeostasis in liver

Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.

2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress

Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis

Project description:Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Lipid reduction through cytoplasmic lipolysis might adversely worsen steatohepatitis, however, the effect of autophagic lipolysis, lipophagy, remains obscure. We engineered the adaptor protein to induce lipophagy with lipid droplet targeting signal and modified LC3 interacting region. Activating hepatocyte lipophagy obviously mitigated both steatosis and NASH pathology. Mechanistically, lipophagy promoted the excretion of lipid from liver via lysosomal exocytosis and attenuated harmful accumulation of nonesterified fatty acid. This exocytosis was dependent on Ca2+ signal unlike the lysosomal dysfunction-related exocytosis. High content compound screening identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin inhibited the transition to steatohepatitis in mice fed high fat with low methionine low choline diet. Given all these data, activating lipophagy may be a promising therapeutic approach to prevent NASH progression.

2023-05-15 | GSE185911 | GEO

Pyruvate kinase M2 controls lipid homeostasis via regulation of SREBPs activation and intestinal cholesterol absorption

Project description:The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer to regulate anabolic metabolism. However, the metabolic requirements of PKM2 in tumorigenesis have yielded contradictory results. Herein we discovered that this glycolytic enzyme regulates lipid homeostasis in cancer cell autonomous manner and at systemic levels. Transmembrane protein 33 (TMEM33) was identified as a downstream effector of PKM2, whose expression level positively correlates with plasma total cholesterol level in vivo. Loss of PKM2 leads to up-regulation of TMEM33, which recruits ring finger protein 5 (RNF5) to promote SCAP ubiquitination and degradation, thereby inhibiting Golgi translocation and activation of sterol regulatory element binding protein 1 (SREBP1). Moreover, global PKM2 knockout promoted allografted tumor growth, at least partially attributes to the elevated plasma cholesterol level caused by increased intestinal Niemann-Pick C1-Like 1 (NPC1L1) to facilitate cholesterol absorption. Collectively, PKM2-TMEM33 axis modulates cell autonomous lipid metabolism by regulating SREBP activation. PKM2 in small intestine plays critical functions in controlling systemic cholesterol level. Overall, our results underscore unappreciated functions of PKM2 in lipid homeostasis and imply that combining an allosteric activator of PKM2 with NPC1L1 inhibitor represents a therapeutic invention for cancer treatment.

2021-08-06 | PXD026434 | Pride

Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption

Project description:Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens recovered components of the known proteostasis network, and uncovered a link between protein and lipid homeostasis. We showed that increased lipid uptake and/or disrupted lipid metabolism led to increased lysosomal, detergent-insoluble protein aggregates and, concomitantly, accumulation of sphingomyelins and cholesterol esters. Proteomic analysis of lysosomes revealed ESCRT accumulation at the lysosomes, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization, but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation impairs proteostasis via ESCRT disruption, potentially as a result of modified membrane properties.

2024-12-20 | PXD054648 | Pride

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