Antigen peptide transporter 1 is involved in the development of fructose‐induced hepatic steatosis in mice

Arindkar, Shailendra; Bhattacharjee, Jashdeep; Kumar, Jerald Mahesh; Das, Balaram; Upadhyay, Pramod; Shajahan, Asif; Juyal, Ramesh C.; Majumdar, Subeer S.; Nagarajan, Priyadharsini

doi:10.1111/jgh.12186

Cited by 16 publications

(10 citation statements)

References 23 publications

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“…We observed that the depletion of CD8+ T‐cells by antibody treatment protects the liver from inflammation, as evident from the lower abundance of both resident and infiltrating macrophages in the liver tissue section and fibrosis as evident from the Masson's trichrome staining of the liver tissue section. Further, the biochemical and histologic improvement observed in our CD8 antibody‐treated mice are in agreement with Arindkar et al We also observed infiltration of CD8+ T‐cells in the liver biopsies of patients with NASH. Although we have not observed infiltration of NKT cells in the liver biopsies of patients with NASH, given the progressive nature of NASH, we cannot be confident that the lack of identification of these cells is the result of transient infiltration of NKT cells.…”

Section: Discussionsupporting

confidence: 92%

Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Bhattacharjee

Kirby

Softic

et al. 2017

Hepatology Communications

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115

114

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Hepatic inflammation is a key pathological feature of Nonalcoholic Steatohepatitis (NASH). Natural Killer T-cells (NKT) and CD8+ T-cells are known to play an important role in obesity related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high fat high carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. Further, to better understand the impact of these cell populations; CD1d-deficient and CD8+ T-cell depleted mice were subjected to HFHC diet for 16 weeks. C57Bl6/J mice fed HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase (ALT) levels and increased NKT cells and CD8+ T-cells infiltration in the liver. In addition human liver sections from patients with NASH showed increased CD8+ T-cells. In comparison, CD1d-deficient and CD8-T cell depleted mice fed HFHC had lower hepatic triglyceride content, lower ALT levels, as well reduced α-smooth muscle actin (αSMA), collagen type 1 alpha 1 (Col1a1), collagen type 1 alpha 2 (Col1a2) mRNA expression, lower activated resident macrophages and infiltrating macrophages and improved NAFLD activity scores. Further, while CD1d-deficient mice were protected against weight gain on the HFHC diet, CD8 T-cell depleted mice gained weight on the HFHC diet. Conclusion We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T-Cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH.

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Section: Discussionsupporting

confidence: 92%

Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Bhattacharjee

Kirby

Softic

et al. 2017

Hepatology Communications

Self Cite

115

114

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“…As described [29–31], insulin tolerance test and glucose intolerance test were performed at 31 weeks of age. An intraperitoneal glucose tolerance test (iGTT) and insulin tolerance test (ITT) were performed on nonanaesthetized mice after 8 hours' fasting.…”

Section: Methodsmentioning

confidence: 99%

Skeletal Muscle-Specific CPT1 Deficiency Elevates Lipotoxic Intermediates but Preserves Insulin Sensitivity

Shi

Wang

et al. 2013

Journal of Diabetes Research

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Objective. By specific knockout of carnitine palmitoyl transferase 1b (CPT1b) in skeletal muscles, we explored the effect of CPT1b deficiency on lipids and insulin sensitivity. Methods. Mice with specific knockout of CPT1b in skeletal muscles (CPT1b M−/−) were used for the experiment group, with littermate C57BL/6 as controls (CPT1b). General and metabolic profiles were measured and compared between groups. mRNA expression and CPT1 activity were measured in skeletal muscle tissues and compared between groups. Mitochondrial fatty acid oxidation (FAO), triglycerides (TAGs), diglycerides (DAGs), and ceramides were examined in skeletal muscles in two groups. Phosphorylated AKT (pAkt) and glucose transporter 4 (Glut4) were determined with real-time polymerase chain reaction (RT-PCR). Insulin tolerance test, glucose tolerance test, and pyruvate oxidation were performed in both groups. Results. CPT1b M−/− model was successfully established, with impaired muscle CPT1 activity. Compared with CPT1b mice, CPT1b M−/− mice had similar food intake but lower body weight or fat mass and higher lipids but similar glucose or insulin levels. Their mitochondrial FAO of skeletal muscles was impaired. There were lipids accumulations (TAGs, DAGs, and ceramides) in skeletal muscle. However, pAkt and Glut4, insulin sensitivity, glucose tolerance, and pyruvate oxidation were preserved. Conclusion. Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity.

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“…CD8 T cells and NK T cells promote NASH and HCC through interactions with hepatocytes (18). CD8 T-cell-depleted mice are protected from the progression of NAFLD (19). In addition to its function as a pore-forming protein, perforin has been shown to play essential roles in immune surveillance, response, and homeostasis, and performs multiple biologic functions in different diseases (20,21).…”

Section: Discussionmentioning

confidence: 99%

The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis

et al. 2019

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The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune‐cell–mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild‐type (WT) mice after 4 wk of feeding on a methionine‐ and choline‐deficient diet (MCD) or 16 wk of feeding on a high‐fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD‐fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non‐CD8 cells or non‐NK cells from WT mice, indicated that CD8 T‐cell–derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin‐deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow‐derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.—Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis. FASEB J. 33, 8490–8503 (2019). http://www.fasebj.org

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Antigen peptide transporter 1 is involved in the development of fructose‐induced hepatic steatosis in mice

Abstract: Taken together, the data suggest that TAP1(-/-) -deficient mice displayed reduced levels of CD8 cells that have a vital role in the initiation and propagation of liver inflammation and is a casual role in the beginning of fructose-induced liver damage as well as insulin resistance in mice.

Cited by 16 publications

References 23 publications

Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Skeletal Muscle-Specific CPT1 Deficiency Elevates Lipotoxic Intermediates but Preserves Insulin Sensitivity

The immunoregulatory effects of CD8 T‐cell–derived perforin on diet‐induced nonalcoholic steatohepatitis

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