Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice

Hui, Simon T.; Gong, Lili; Swichkow, Chantle; Blencowe, Montgomery; Kaminska, Dorota; Diamante, Graciel; Pan, Calvin; Dalsania, Meet; French, Samuel W.; Magyar, Clara E.; Pajukanta, Päivi; Pihlajamäki, Jussi; Boström, Kristina I.; Yang, Xia; Lusis, Aldons J.

doi:10.1016/j.jcmgh.2023.08.007

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…MGP, an extracellular matrix protein that inhibits calcification ( 49 ), has only recently been implicated in MASLD. Research by Hui et al ( 50 ) showed that hepatic Mgp expression increased in tandem with MASH progression in a mouse model and was significantly correlated with fibrosis severity in humans with MASH ( 50 ). Mgp was highly expressed in HSC and identified as a key driver for liver fibrosis through network modeling, associated with the regulators of fibrosis, Loxl1 , Smoc2 , and Itgbl1 ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

Piras,

DiStefano

2024

Life Sci. Alliance

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Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), pose significant risks of severe fibrosis, cirrhosis, and hepatocellular carcinoma. Despite their widespread prevalence, the molecular mechanisms underlying the development and progression of these common chronic hepatic conditions are not fully understood. Here, we conducted the most extensive meta-analysis of hepatic gene expression datasets from liver biopsy samples to date, integrating 10 RNA-sequencing and microarray datasets (1,058 samples). Using a random-effects meta-analysis model, we compared over 12,000 shared genes across datasets. We identified 685 genes differentially expressed in MASLD versus normal liver, 1,870 in MASH versus normal liver, and 3,284 in MASLD versus MASH. Integrating these results with genome-wide association studies and coexpression networks, we identified two functionally relevant, validated coexpression modules mainly driven by SMOC2, ITGBL1, LOXL1, MGP, SOD3, and TAT, HGD, SLC25A15, respectively, the latter not previously associated with MASLD and MASH. Our findings provide a comprehensive and robust analysis of hepatic gene expression alterations associated with MASLD and MASH and identify novel key drivers of MASLD progression.

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Section: Discussionmentioning

confidence: 99%

Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

Piras,

DiStefano

2024

Life Sci. Alliance

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“…However, similar to the heterogeneity of human NAFLD/NASH, pathogenesis of NAFLD also varies significantly in different strains of mice in response to diet. 5 In this issue of Cellular and Molecular Gastroenterology and Hepatology , Hui et al 6 used an elegant hybrid mouse diversity panel that contains more than 100 inbred strains of mice. They used a "systems genetics" approach that integrated clinical and molecular traits with genetic mapping, correlating, and statistical modeling to identify matrix Gla protein (MGP) as a new target for NASH-associated fibrosis.…”

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confidence: 99%

“…Homozygous MGP-knockout mice die at approximately 2 months old owing to aberrant cartilage and arterial calcification. 7 Using the global transcriptomic profiling of livers from the hybrid mouse diversity panel, Hui et al 6 found that hepatic expression of Mgp was associated with liver fibrosis in both male and female mice. The expression of Mgp increased with time and correlated with the severity of NASH in mice and NASH patients.…”

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confidence: 99%

Matrix Gla Protein, a New Target Fighting Against Fibrosis of Nonalcoholic Steatohepatitis?

Hinz,

Ding

2023

Cellular and Molecular Gastroenterology and Hepatology

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Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multi-compartmental alterations in gene expression and signaling cross-talk

Sun,

Kraus,

Zhao

et al. 2024

Preprint

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Vulvar diseases are a critical yet often neglected area of women's health, profoundly affecting patients' quality of life and frequently resulting in long-term physical and psychological challenges. Lichen sclerosus (LS) is a chronic inflammatory skin disorder that predominantly affects the vulva, leading to severe itching, pain, scarring, and an increased risk of malignancy. Despite its profound impact on affected individuals, the molecular pathogenesis of vulvar LS (VLS) is not well understood, hindering the development of FDA-approved therapies. Here, we utilize single-cell and spatial transcriptomics to analyze lesional and non-lesional skin from VLS patients, as well as healthy control vulvar skin. Our findings demonstrate histologic, cellular, and molecular heterogeneities within VLS, yet highlight unifying molecular changes across keratinocytes, fibroblasts, immune cells, and melanocytes in lesional skin. They reveal cellular stress and damage in fibroblasts and keratinocytes, enhanced T cell activation and cytotoxicity, aberrant cell-cell signaling, and increased activation of the IFN, JAK/STAT, and p53 pathways in specific cell types. Using both monolayer and organotypic culture models, we also demonstrate that knockdown of select genes, which are downregulated in VLS lesional keratinocytes, partially recapitulates VLS-like stress-associated changes. Collectively, these data provide novel insights into the pathogenesis of VLS, identifying potential biomarkers and therapeutic targets for future research.

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Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice

Cited by 3 publications

References 53 publications

Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

Matrix Gla Protein, a New Target Fighting Against Fibrosis of Nonalcoholic Steatohepatitis?

Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multi-compartmental alterations in gene expression and signaling cross-talk

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