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Dynamics of Liver Macrophage Subsets in a Novel Mouse Model of Non-Alcoholic Steatohepatitis Using C57BL/6 Mice.

ABSTRACT: Macrophages are critical for the development of non-alcoholic steatohepatitis (NASH). Our previous findings in TSNO mouse livers showed that an iHFC (high-fat/cholesterol/cholate) diet induced liver fibrosis similar to human NASH and led to the accumulation of distinct subsets of macrophage: CD11c⁺/Ly6C^- and CD11c^-/Ly6C⁺ cells. CD11c⁺/Ly6C^- cells were associated with the promotion of advanced liver fibrosis in NASH. On the other hand, CD11c^-/Ly6C⁺ cells exhibited an anti-inflammatory effect and were involved in tissue remodeling processes. This study aimed to elucidate whether an iHFC diet with reduced cholic acid (iHFC#2 diet) induces NASH in C57BL/6 mice and examine the macrophage subsets accumulating in the liver. Histological and quantitative real-time PCR analyses revealed that the iHFC#2 diet promoted inflammation and fibrosis indicative of NASH in the livers of C57BL/6 mice. Cell numbers of Kupffer cells decreased and recruited macrophages were accumulated in the livers of iHFC#2 diet-fed C57BL/6 mice. Notably, the iHFC#2 diet resulted in the accumulation of three macrophage subsets in the livers of C57BL/6 mice: CD11c⁺/Ly6C^-, CD11c^-/Ly6C⁺, and CD11c⁺/Ly6C⁺ cells. However, CD11c⁺/Ly6C⁺ cells were not distinct populations in the iHFC-fed TSNO mice. Thus, differences in cholic acid content and mouse strain affect the macrophage subsets that accumulate in the liver.

SUBMITTER: Makiuchi N

PROVIDER: S-EPMC10604124 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Dynamics of Liver Macrophage Subsets in a Novel Mouse Model of Non-Alcoholic Steatohepatitis Using C57BL/6 Mice.

Makiuchi Nana N Takano Shun S Tada Yuki Y Kasai Kaichi K Igarashi Naoya N Kani Koudai K Kato Miyuna M Goto Kana K Matsuura Yudai Y Ichimura-Shimizu Mayuko M Furusawa Yukihiro Y Tsuneyama Koichi K Nagai Yoshinori Y

Biomedicines 20230928 10

Macrophages are critical for the development of non-alcoholic steatohepatitis (NASH). Our previous findings in TSNO mouse livers showed that an iHFC (high-fat/cholesterol/cholate) diet induced liver fibrosis similar to human NASH and led to the accumulation of distinct subsets of macrophage: CD11c+/Ly6C- and CD11c-/Ly6C+ cells. CD11c+/Ly6C- cells were associated with the promotion of advanced liver fibrosis in NASH. On the other h ...[more]

PMID: 37893033

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Project description:Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

Dataset Information

Dynamics of Liver Macrophage Subsets in a Novel Mouse Model of Non-Alcoholic Steatohepatitis Using C57BL/6 Mice.

Publications

Dynamics of Liver Macrophage Subsets in a Novel Mouse Model of Non-Alcoholic Steatohepatitis Using C57BL/6 Mice.

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