Hepatocyte-specific depletion of Nnmt protects mice from non-alcoholic steatohepatitis

Li, Dandan; Yi, Chuanyou; Huang, He; Li, Jin; Hong, Shangyu

doi:10.1016/j.jhep.2022.03.021

Cited by 8 publications

(5 citation statements)

References 7 publications

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“…4B–C ). Since hepatocyte apoptosis strongly correlates with MASH progression, 30 we next determined whether RvD1 prevents apoptosis in primary hepatocytes. Primary hepatocytes were incubated with palmitic acid, 31 a MASH-relevant saturated fatty acid that can elicit lipotoxicity and apoptotic cell death, in the absence or presence of RvD1.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Activity of Resolvin D1 (RvD1) in Murine MASH

Navarro-Corcuera,

Zhu,

et al. 2024

Preprint

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Background and Aims: Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression. Methods: RvD1 was administered to mice with experimental MASH, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to elucidate the effect of RvD1 on inflammation, cell death, and fibrosis regression genes. Results: Hepatic tissue levels of RvD1 were decreased in murine and human MASH, likely due to an expansion of pro-inflammatory M1-like macrophages with diminished ability to produce RvD1. Administering RvD1 reduced inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the Stat1-Cxcl10 signaling pathway in macrophages and prevented hepatocyte death by alleviating ER stress-mediated apoptosis. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH. Conclusions: RvD1 reduces Stat1-mediated inflammation, mitigates ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. This study highlights the therapeutic potential of RvD1 to treat MASH.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Activity of Resolvin D1 (RvD1) in Murine MASH

Navarro-Corcuera,

Zhu,

et al. 2024

Preprint

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“…Furthermore, investigations in NASH mice with NNMT knockout (NNMT-LKO) revealed notable reductions in total cholesterol levels, low-density lipoprotein levels, liver weight, liver inflammation, and fibrosis levels. Further analysis revealed that the levels of liver damage markers in the serum of NNMT-LKO mice were significantly decreased (Li et al 2022 ). These findings imply a potential association between reduced 1-MNAM levels in HCC and NNMT, and the suppression of NNMT expression could be linked to the liver steatosis-inflammation-cancer axis.…”

Section: Discussionmentioning

confidence: 99%

Identification of 1-Methylnicotinamide as a specific biomarker for the progression of cirrhosis to hepatocellular carcinoma

Zhang,

Tuo,

et al. 2024

J Cancer Res Clin Oncol

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Purpose Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, often arising from hepatitis induced by the hepatitis B virus (HBV) in China. However, effective biomarkers for early diagnosis are lacking, leading to a 5-year overall survival rate of less than 20% among patients with advanced HCC. This study aims to identify serum biomarkers for early HCC diagnosis to enhance patient survival rates. Methods We established an independent cohort comprising 27 healthy individuals, 13 patients with HBV-induced cirrhosis, 13 patients with hepatitis B-type HCC, and 8 patients who progressed from cirrhosis to hepatocellular carcinoma during follow-up. Serum metabolic abnormalities during the progression from cirrhosis to HCC were studied using untargeted metabolomics. Liquid chromatography-mass spectrometry-based metabolomics methods characterized the subjects’ serum metabolic profiles. Partial least squares discriminant analysis (PLS-DA) was employed to elucidate metabolic profile changes during the progression from cirrhosis to HCC. Differentially expressed metabolites (DEMs) between cirrhosis and HCC groups were identified using the LIMMA package in the R language. Two machine learning algorithms, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest Classifier (RF), were used to identify key metabolic biomarkers involved in the progression from cirrhosis to HCC. Key metabolic biomarkers were further validated using targeted metabolomics in a new independent validation cohort comprising 25 healthy individuals and 25 patients with early-stage hepatocellular carcinoma. Results A total of 155 serum metabolites were identified, of which 21/54 metabolites exhibited significant changes in HCC patients compared with cirrhosis patients and healthy individuals, respectively. PLS-DA clustering results demonstrated a significant change trend in the serum metabolic profile of patients with HBV-induced cirrhosis during the progression to HCC. Utilizing LASSO regression and RF algorithms, we confirmed 10 key metabolic biomarkers. Notably, 1-Methylnicotinamide (1-MNAM) exhibited a persistent and significant decrease in healthy individuals, cirrhosis, and HCC patients. Moreover, 1-MNAM levels in developing patients were significantly higher during the cirrhosis stage than in the HCC stage. Targeted metabolomic validation in an external cohort further confirmed the good diagnostic performance of 1-MNAM in early HCC detection. Conclusion Our findings imply that 1-MNAM may be a specific biomarker for the progression of cirrhosis to HCC.

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“…Substantial studies have demonstrated the advantages of boosting NAD+ and hepatocyte-specific Nnmt deletion in liver diseases ( Song et al 2020 , Mukherjee et al 2021 , Li et al 2022 ). Although no inflammatory genes were changed, MNAM reduced lipid accumulation and ameliorated hepatic function, which further confirmed improved hepatic NAD+ metabolism.…”

Section: Discussionmentioning

confidence: 99%

N1-methylnicotinamide impairs gestational glucose tolerance in mice

Wei,

Tan,

Huang

et al. 2023

Journal of Molecular Endocrinology

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N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays anti-diabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with high fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired the glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, it reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. NAD+/Sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was deminished in placenta by MNAM. In addition, weight of placenta, fetus weight or litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of GTT by MNAM. Our data provide evidences for the careful usage of MNAM in treatment of GDM.

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Hepatocyte-specific depletion of Nnmt protects mice from non-alcoholic steatohepatitis

Cited by 8 publications

References 7 publications

Therapeutic Activity of Resolvin D1 (RvD1) in Murine MASH

Therapeutic Activity of Resolvin D1 (RvD1) in Murine MASH

Identification of 1-Methylnicotinamide as a specific biomarker for the progression of cirrhosis to hepatocellular carcinoma

N1-methylnicotinamide impairs gestational glucose tolerance in mice

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