Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

Larsen, Frederik; Hansen, Daniel; Terkelsen, Mike Krogh; Bendixen, Sofie M.; Avolio, Fabio; Wernberg, Charlotte; Lauridsen, Mette E.M.; Grønkjær, Lea Ladegaard; Jacobsen, Birgitte G.; Gammelmark, Ellen; Mandrup, Susanne; Caterino, Tina Di; Siersbæk, Majken; Chandran, Vineesh Indira; Graversen, Jonas Heilskov; Krag, Aleksander; Grøntved, Lars; Ravnskjær, Kim

doi:10.1016/j.jhepr.2022.100615

Cited by 10 publications

(6 citation statements)

References 53 publications

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“…Among these, the role of SMOC2 piqued our interest. As previously reported, SMOC2 plays a significant role in liver, kidney, and lung fibrosis [12,32,33]. However, studies on the role of SMOC2 in myocardial fibrosis are limited.…”

Section: Discussionmentioning

confidence: 90%

“…SMOC2, a SPARC-related modular calcium-binding protein 2, is an encoded modular secretion protein that can affect the activity of cytokines, destroy the attachment of cell substrates, and regulate cell differentiation and cell cycle [10,11]. SMOC2 is reportedly involved in the regulation of fibrotic diseases [12][13][14]. Moreover, SMOC2 suppression has been shown to alleviate myocardial fibrosis via the ILK/p38 pathway [15].…”

Section: Introductionmentioning

confidence: 99%

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METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

He,

Pan,

Tao

et al. 2024

Preprint

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Cardiac fibrosis leads to decreased cardiac compliance, impaired systolic and diastolic function, resulting in heart failure. M6A methylation plays a role in fibrosis development. However, its underlying mechanism remain poorly understood. This study explores the role and molecular mechanisms of m6A methylation in regulating cardiac fibrosis after myocardial infarction (MI). A mouse myocardial fibrosis model post-MI was established by ligating the left coronary artery. Corresponding gene knockdown was achieved in vitro or in vivo using short hairpin RNA or fibroblast-specific AAV9 virus. Echocardiography assessed cardiac function in mice, while Masson staining determined the degree of collagen deposition post-MI. The meRIP-Seq kit detected mRNA methylation levels in myocardial tissue and hypoxia-treated cardiac fibroblasts. Expression of RNA methylation-related enzymes, fibrosis-related proteins, and SMOC2 expression in the myocardial tissue or cardiac fibroblasts was detected using western blotting. Actinomycin D assessed SMOC2 mRNA stability. Results demonstrated increased levels of m6A methylation and METTL3 expression in myocardial fibrosis tissue post-MI and in hypoxia-treated cardiac fibroblasts. In vivo METTL3 downregulation reduced the fibrotic area and improved cardiac function, while METTL3 downregulation in vitro can alleviate cardiac fibroblast proliferation and differentiation after hypoxia. Per bioinformatic analysis, SMOC2 may be differentially expressed, regulated by RNA methylation during cardiac fibroblast proliferation and differentiation. SMOC2 is significantly elevated in myocardial fibrotic tissue post-MI and hypoxia-induced cardiac fibroblasts. SMOC2 downregulation alleviates cardiac fibroblast proliferation and differentiation. Mechanistically, METTL3 promoted SMOC2 mRNA stability by increasing its m6A methylation level, thereby regulating cardiac fibroblast proliferation and differentiation. Conclusively, METTL3 participates in cardiac fibroblasts proliferation and differentiation post-MI by increasing the m6A methylation level of SMOC2 mRNA, thereby promoting its stability.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

He,

Pan,

Tao

et al. 2024

Preprint

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“…Notably, SMOC2 -knockout mice exhibited protection against liver fibrosis and reduced hepatic inflammation induced by HFD ( 37 ). Larsen et al ( 38 ) recently observed elevated hepatic and plasma levels of SMOC2 in individuals with MASH compared to those without MASLD and showed that SMOC2 is primarily expressed by hepatic stellate cells, which play a pivotal role in fibrogenesis. SMOC2 levels were also elevated in hepatocellular carcinoma tissue relative to normal tissue, and SMOC2 overexpression promoted hepatocellular carcinoma cell proliferation ( 39 ).…”

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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“…Whether or not a similar mechanism was involved in our study still needs further investigation. Hepatic fibrosis is an advanced stage of NAFLD progression and HSCs are the key matrix-producing cells in liver and play a central role in hepatic fibrogenesis (35). Our previous study demonstrated that galanin inhibits HSCs activation and suppresses their profibrogenic features (16).…”

Section: Discussionmentioning

confidence: 99%

Galanin ameliorates liver inflammation and fibrosis in mice by activating AMPK/ACC signaling and modifying macrophage inflammatory phenotype

Huang

Wang

et al. 2023

Front. Immunol.

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Background and aimsGalanin is a naturally occurring peptide that plays a critical role in regulating inflammation and energy metabolism, with expression in the liver. The exact involvement of galanin in non-alcoholic fatty liver disease and related fibrosis remains controversial.MethodsThe effects of subcutaneously administered galanin were studied in mice with non-alcoholic steatohepatitis (NASH) induced by a high-fat and high-cholesterol diet for 8 weeks, and in mice with liver fibrosis induced by CCl4 for 7 weeks. The underlying mechanism was also studied in vitro on murine macrophage cells (J774A.1 and RAW264.7).ResultsGalanin reduced inflammation, CD68-positive cell count, MCP-1 level, and mRNA levels of inflammation-related genes in the liver of NASH mice. It also mitigated liver injury and fibrosis caused by CCl4. In vitro, galanin had anti-inflammatory effects on murine macrophages, including reduced phagocytosis and intracellular reactive oxygen species (ROS). Galanin also activated AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling.ConclusionGalanin ameliorates liver inflammation and fibrosis in mice, potentially by modifying macrophage inflammatory phenotype and activating AMPK/ACC signaling.

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Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

Cited by 10 publications

References 53 publications

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

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

Galanin ameliorates liver inflammation and fibrosis in mice by activating AMPK/ACC signaling and modifying macrophage inflammatory phenotype

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