Dataset Information

Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation

ABSTRACT: use serum lipids panel to distinguish human fibrosis and non-fibrosis liver

ORGANISM(S): Homo Sapiens

SUBMITTER: Guanghou Shui

PROVIDER: PXD051283 | iProX | Thu Jun 27 00:00:00 BST 2024

REPOSITORIES: iProX

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Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation.

Lam Sin Man SM Wang Zehua Z Song Jin-Wen JW Shi Yue Y Liu Wen-Yue WY Wan Lin-Yu LY Duan Kaibo K Chua Gek Huey GH Zhou Yingjuan Y Wang Guibin G Huang Xiahe X Wang Yingchun Y Wang Fu-Sheng FS Zheng Ming-Hua MH Shui Guanghou G

Cell metabolism 20241104 1

There exists a pressing need for a non-invasive panel that differentiates mild fibrosis from non-fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). In this work, we applied quantitative lipidomics and sterolomics on sera from the PERSONS cohort with biopsy-based histological assessment of liver pathology. We trained a lasso regression model using quantitative omics data and clinical variables, deriving a combinatorial panel of lipids and clinical indices that different ...[more]

PMID: 39500328

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Project description:Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2 cells (ANGPTL3-/-) whereupon we observed ∼50% reduction of apolipoprotein B100 (ApoB100) secretion, accompanied by an increase in ApoB100 early presecretory degradation via a predominantly lysosomal mechanism. Despite defective particle secretion in ANGPTL3-/- cells, targeted lipidomic analysis did not reveal neutral lipid accumulation in ANGPTL3-/- cells; rather ANGPTL3-/- cells demonstrated decreased secretion of newly synthesized triglycerides and increased fatty acid oxidation. Furthermore, RNA sequencing demonstrated significantly altered expression of key lipid metabolism genes, including targets of peroxisome proliferator-activated receptor α, consistent with decreased lipid anabolism and increased lipid catabolism. In contrast, CRISPR/Cas9 LDL receptor (LDLR) deletion in ANGPTL3-/- cells did not result in a secretion defect at baseline, but proteasomal inhibition strongly induced compensatory late presecretory degradation of ApoB100 and impaired its secretion. Additionally, these ANGPTL3-/-;LDLR-/- cells rescued the deficient LDL clearance of LDLR-/- cells. In summary, ANGPTL3 deficiency in the presence of functional LDLR leads to the production of fewer lipoprotein particles due to early presecretory defects in particle assembly that are associated with adaptive changes in intrahepatic lipid metabolism. In contrast, when LDLR is absent, ANGPTL3 deficiency is associated with late presecretory regulation of ApoB100 degradation without impaired secretion. Our findings therefore suggest an unanticipated intrahepatic role for ANGPTL3, whose function varies with LDLR status.

Dataset Information

Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation

Publications

Non-invasive lipid panel of MASLD fibrosis transition underscores the role of lipoprotein sulfatides in hepatic immunomodulation.

Similar Datasets

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