SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface

Zhao, Nan; Zhang, Xiaoxun; Ding, Jingjing; Pan, Qiong; Zheng, Ming‐Hua; Liu, Wen-Yue; Luo, Gang; Qu, Jiaquan; Li, Mingqiao; Li, Ling; Cheng, Ying; Peng, Ying; Zhang, Xiaoxun; Wei, Qinglin; Li, Qiao; Zou, Lingyun; Ouyang, Xinshou; Cai, Shi‐Ying; Boyer, James L.; Chai, Jin

doi:10.1172/jci.insight.154113

Cited by 10 publications

(4 citation statements)

References 32 publications

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“…Sterol regulatory element-binding protein 1 (SREBP1) is a crucial factor in the regulation of fatty acid metabolism. The overexpression of SREBP1 and its downstream target genes, including stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (FAS), contributes to an increased synthesis of triglycerides, thereby leading to the accumulation of fat in the liver. , LXRα plays a significant role in the stimulation of fatty acid and triglyceride biosynthesis by directly controlling the crucial adipogenic factors such as SREBP1, FASN, and SCD1, and this is one of the main reasons for the limited clinical efficacy of LXR agonists in the treatment of hypercholesterolemia. , Consequently, an ideal potential therapeutic agent for hypercholesterolemia through LXR activation should possess the characteristic of selectively activating LXRα while avoiding the induction of SREBP1 expression …”

Section: Resultsmentioning

confidence: 99%

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

Fang,

She,

Zhang

et al. 2024

J. Nat. Prod.

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A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.

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Section: Resultsmentioning

confidence: 99%

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

Fang,

She,

Zhang

et al. 2024

J. Nat. Prod.

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“…Recently it was shown that SEMA7A is crucial for inflammation resolution by promoting polarization of activated macrophages toward the pro-resolving M2 phenotype, leukocyte clearance, and generation of specialized pro-resolving lipid mediators [ 39 ]. Interestingly, it was demonstrated that the SEMA7A R148W mutation is a potentially new genetic determinant of NAFLD that promotes intrahepatic lipid accumulation in mice [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD.

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“…All identified proteins were determined using a false discovery rate (FDR) threshold of <0.01. After retrieval from the UniProtKB database and searching against the SwissProt database (mouse), the top BLAST hits were processed for GO enrichment analysis using Blast2GO (BioBam, Valencia, Spain; version 3.3.5) [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

A de novo missense mutation in MPP2 confers an increased risk of Vogt–Koyanagi–Harada disease as shown by trio-based whole-exome sequencing

Liu,

Meng,

Liao

et al. 2023

Cell Mol Immunol

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Vogt–Koyanagi–Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.

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SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface

Cited by 10 publications

References 32 publications

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

A de novo missense mutation in MPP2 confers an increased risk of Vogt–Koyanagi–Harada disease as shown by trio-based whole-exome sequencing

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