Optimization of In vivo Imaging Provides a First Look at Mouse Model of Non-Alcoholic Fatty Liver Disease (NAFLD) Using Intravital Microscopy

Davis, Rachelle P.; Surewaard, Bas G.J.; Turk, Madison; Carestia, Agostina; Lee, Woo Yong; Petri, Bjӧrn; Urbanski, Stefan J.; Coffin, Carla S.; Jenne, Craig N.

doi:10.3389/fimmu.2019.02988

Cited by 18 publications

(22 citation statements)

References 44 publications

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“…Insulin resistance was found to be an independent predictor of NAFLD [8], and the HOMA-IR index was found to be significantly increased in the high-fat-induced model group of mice in this study. ese results are consistent with what has been demonstrated by previous studies [9]. Intervention with Lanzhang Granules for 8 weeks significantly reduced body weight, liver weight, and liver index.…”

Section: Discussionsupporting

confidence: 92%

Lanzhang Granules Ameliorate Nonalcoholic Fatty Liver Disease by Regulating the PPARα Signaling Pathway

Huang

Yang

Liu

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. There is still a lack of effective therapeutic drugs for nonalcoholic fatty liver disease (NAFLD) to date. In this study, we applied mouse model experiments to clarify the effect of Chinese herbal medicine “Lanzhang Granules (LZG)” on NAFLD and further explore the potential mechanism to provide an alternative method for NAFLD treatment. Methods. Male C57BL/6J mice were fed with a high-fat diet (HFD) for twenty-two weeks to induce the NAFLD model. LZG intervention was then performed by gavage daily for another eight weeks. At the end of the treatment, serum and liver tissues were collected. Serum biochemical indexes, insulin levels, and liver histopathology were measured to assess the effect of LZG on NAFLD. The liver tissues were then analyzed by RNA sequence for differentially expressed genes and signaling pathways. Results were further analyzed by Protein-Protein Interaction (PPI) networks between the LZG and model groups. The selected different genes and signaling pathways were further verified by RT-PCR and Western blot analysis. Moreover, alpha mouse liver 12 (AML12) cells with lipid accumulation induced by fatty acid were treated with LZG, Fenofibrate (PPARα agonist), or Gw6471 (PPARα antagonist) to confirm the potential pharmacological mechanism. Results. LZG was found to downregulate liver weight, body weight, liver index, and serum levels of ALT, AST, and serum lipid in HFD-induced NAFLD mice. HE and Oil Red O staining showed the improvement of hepatic steatosis and inflammatory infiltration in the mice with LZG treatment. The homeostasis model assessment-insulin resistance (HOMA-IR) index indicated that LZG improved the insulin resistance of NAFLD mice. The RNA sequencing and PPI analysis confirmed the role of LZG in lipid metabolism regulation and identified the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway as one of the major underlying mechanisms. Western blot and RT-PCR results verified the regulatory effect of LZG on the PPARα pathway, including the upregulation of PPARα, acyl-coenzyme A oxidase 1 (ACOX1), and enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase (EHHADH) and the downregulation of TNFα. In vitro experiments showed the effect of LZG in improving lipid accumulation and cell viability in AML12 cells induced by fatty acids, which were alleviated by Gw6471 coincubation. Gw6471could also reverse the transcription of PPAR target genes ACOX1 and EHHADH, which were upregulated by LZG treatment. Conclusion. LZG can improve NAFLD in mice or cell models. A major underlying mechanism may be the regulation of the PPARα signaling pathway to improve lipid metabolism and inhibit the inflammatory response. This study will help to promote the clinical application of LZG for the treatment of NAFLD.

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Section: Discussionsupporting

confidence: 92%

Lanzhang Granules Ameliorate Nonalcoholic Fatty Liver Disease by Regulating the PPARα Signaling Pathway

Huang

Yang

Liu

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…All experiments were approved by the University of Calgary animal care committee in accordance with the Canadian Council for Animal care (AC16-0040). C57BL/6 male mice (6–8 weeks old, N = 40;10/group), were fed either a normal chow vs. HFD (40% fat, 40% sucrose, Dyets Inc., Bethelem, PA) 47 and administered 2 doses of Engerix-B ® (0.05 µg/g body weight) 2 weeks apart, intramuscularly, either after inducing NAFLD phenotype (N→V) or at baseline prior to HFD (V→N). The induction of NAFLD phenotype in mice was confirmed on liver histology.…”

Section: Methodsmentioning

confidence: 99%

Reduced immune responses to hepatitis B primary vaccination in obese individuals with nonalcoholic fatty liver disease (NAFLD)

et al. 2021

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Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B®, or Twinrix®, GlaxoSmithKline). Anti-HBs titers were measured at 1–3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses.

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“…Surgical preparation of animals for liver intravital microscopy was performed as previously described ( 33 ). B cells were visualized with the use of CD19-ZsGreen or CD19-tdTomato reporter mice, or by labelling with Brilliant Violet 421- conjugated anti-mouse CD19 (6D5) antibodies (Biolegend).…”

Section: Methodsmentioning

confidence: 99%

The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse

et al. 2021

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IntroductionB cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro.ConclusionMirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology.

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Optimization of In vivo Imaging Provides a First Look at Mouse Model of Non-Alcoholic Fatty Liver Disease (NAFLD) Using Intravital Microscopy

Cited by 18 publications

References 44 publications

Lanzhang Granules Ameliorate Nonalcoholic Fatty Liver Disease by Regulating the PPARα Signaling Pathway

Lanzhang Granules Ameliorate Nonalcoholic Fatty Liver Disease by Regulating the PPARα Signaling Pathway

Reduced immune responses to hepatitis B primary vaccination in obese individuals with nonalcoholic fatty liver disease (NAFLD)

The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse

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