bims-nastce Biomed News
on NASH and T cells
Issue of 2021–10–24
six papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Diet and gut microbiome in fatty liver and its associated liver cancer.
  2. MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication between Kupffer Cells and Tregs.
  3. New targets for NAFLD.
  4. Gut Microbiota-Related Cellular and Molecular Mechanisms in the Progression of Nonalcoholic Fatty Liver Disease.
  5. Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice.
  6. C-C chemokine ligand 3 deficiency ameliorates diet-induced Steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice.
  1. J Gastroenterol Hepatol. 2021 Oct 19.
    Diet and gut microbiome in fatty liver and its associated liver cancer.
    Yasi Pan, Xiang Zhang.
      Non-alcoholic fatty liver disease (NAFLD) is the major cause of chronic liver disease worldwide as a consequence of a sedentary lifestyle and overnutrition. NAFLD could progress to non-alcoholic steatohepatitis (NASH), which may further develop to cirrhosis and hepatocellular carcinoma (HCC). The gut microbiome is one of the central regulators in host metabolism. Diet could change human gut microbiome rapidly and reproducibly and modulate several metabolic pathways. Both diet and gut microbiome dysbiosis are associated with NAFLD and its related HCC (NAFLD-HCC). Dietary cholesterol, fiber, fat or carbohydrate could change the microbiome composition to contribute to the development of NASH and NAFLD-HCC. Hence, identification of elements of the gut-liver axis that are primarily damaged in NASH and NAFLD-HCC offers new possibility for therapeutic intervention. In this review, the roles of gut microbiome and microbial metabolites in the development and progression of NAFLD and NAFLD-HCC are first discussed. The impacts of different diet compositions including cholesterol, fiber, fat and sugar on the gut microbiome which leads to predisposition to NASH and NAFLD-HCC are also explored. We summarized the article by discussing potential therapeutic implication of diet and microbiome modulation in fatty liver and liver cancer.
    Keywords:  Diet; Gut microbiome; HCC; NASH
    DOI:  https://doi.org/10.1111/jgh.15713
  2. Gastroenterology. 2021 Oct 19. pii: S0016-5085(21)03652-0. [Epub ahead of print]
    MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication between Kupffer Cells and Tregs.
    Ningning Liu, Ching Wen Chang, Clifford J Steer, Xin Wei Wang, Guisheng Song.
       BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is characterized by intratumoral accumulation of regulatory T-cells (Tregs), which suppresses antitumor immunity. This study was designed to investigate how microRNAs regulate immunosuppression in HCC.
    METHODS: FVB/NJ mice were hydrodynamically injected with AKT/Ras or c-Myc and Sleeping Beauty transposon to induce HCC. The Sleeping Beauty system was used to deliver microRNA-15a/16-1 into livers of mice. Flow cytometry and immunostaining were used to determine changes in the immune system.
    RESULTS: Hydrodynamic injection (HDI) of AKT/Ras or c-Myc into mice resulted in hepatic enrichment of Tregs, reduced cytotoxic T cells (CTLs) and HCC development. HCC impaired microRNA-15a/16-1 biogenesis in Kupffer cells (KCs) of AKT/Ras and c-Myc mice. HDI of microRNA-15a/16-1 fully prevented HCC in AKT/Ras and c-Myc mice, while 100% of control mice died from HCC. Therapeutically, microRNA-15a/16-1 promoted a regression of HCC in both mouse models. MicroRNA-15a/16-1 impaired hepatic enrichment of Tregs and increased hepatic CTLs. Mechanistically, a significant increase was observed in serum C-C motif chemokine 22 (CCL22) and transcription of Ccl22 in KCs of AKT/Ras and c-Myc mice. MicroRNA-15a/16-1 prevented KCs from overproducing CCL22 by inhibiting NF-κB that activates transcription of Ccl22. By reducing CCL22 binding to CCR4 on Tregs, microRNA-15a/16-1 impaired Treg chemotaxis. Disrupting the interaction between microRNA-15a/16-1 and NF-κB impaired the ability of microRNA-15a/16-1 to prevent hepatic Treg accumulation and HCC. Depletion of CD8+ T cells and additional treatment of CCL22 recovered growth of HCC that was fully prevented by miR-15a/16.
    CONCLUSION: MicroRNA-15a/16-1 attenuates immunosuppression by disrupting CCL22-mediated communication between KCs and Tregs. MicroRNA-15a/16-1 represents a potential immunotherapy against HCC.
    Keywords:  Immunosuppression; Kupffer cells; immunotherapy; microRNA
    DOI:  https://doi.org/10.1053/j.gastro.2021.10.015
  3. JHEP Rep. 2021 Dec;3(6): 100346
    New targets for NAFLD.
    Lucia Parlati, Marion Régnier, Hervé Guillou, Catherine Postic.
      Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide. It is characterised by steatosis, liver inflammation, hepatocellular injury and progressive fibrosis. Several preclinical models (dietary and genetic animal models) of NAFLD have deepened our understanding of its aetiology and pathophysiology. Despite the progress made, there are currently no effective treatments for NAFLD. In this review, we will provide an update on the known molecular pathways involved in the pathophysiology of NAFLD and on ongoing studies of new therapeutic targets.
    Keywords:  ACC, acetyl-CoA carboxylase; ASK1, apoptosis signal-regulating kinase 1; CAP, controlled attenuation parameter; ChREBP; ChREBP, carbohydrate responsive element–binding protein; FAS, fatty acid synthase; FFA, free fatty acid; FGF21, fibroblast growth factor-21; FXR; FXR, farnesoid X receptor; GGT, gamma glutamyltransferase; HCC, hepatocellular carcinoma; HFD, high-fat diet; HSC, hepatic stellate cells; HSL, hormone-sensitive lipase; HVPG, hepatic venous pressure gradient; IL-, interleukin-; JNK, c-Jun N-terminal kinase; LXR; LXR, liver X receptor; MCD, methionine- and choline-deficient; MUFA, monounsaturated fatty acids; NAFLD; NAFLD, non-alcoholic fatty liver disease; NASH; NASH, non-alcoholic steatohepatitis; NEFA; NEFA, non-esterified fatty acid; PPARα; PPARα, peroxisome proliferator-activated receptor-α; PUFAs, polyunsaturated fatty acids; PY, persons/years; Phf2, histone demethylase plant homeodomain finger 2; RCT, randomised controlled trial; SCD1, stearoyl-CoA desaturase-1; SFA, saturated fatty acid; SREBP-1c; SREBP-1c, sterol regulatory element–binding protein-1c; TCA, tricarboxylic acid; TLR4, Toll-like receptor 4; TNF-α, tumour necrosis factor-α; VLDL, very low-density lipoprotein; animal models; glucotoxicity; lipotoxicity
    DOI:  https://doi.org/10.1016/j.jhepr.2021.100346
  4. Cells. 2021 Oct 02. pii: 2634. [Epub ahead of print]10(10):
    Gut Microbiota-Related Cellular and Molecular Mechanisms in the Progression of Nonalcoholic Fatty Liver Disease.
    Eunju Park, Jin-Ju Jeong, Sung-Min Won, Satya Priya Sharma, Yoseph Asmelash Gebru, Raja Ganesan, Haripriya Gupta, Ki Tae Suk, Dong Joon Kim.
      Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide. NAFLD is a term that involves a variety of conditions such as fatty liver, steatohepatitis, or fibrosis. Gut microbiota and its products have been extensively studied because of a close relation between NAFLD and microbiota in pathogenesis. In the progression of NAFLD, various microbiota-related molecular and cellular mechanisms, including dysbiosis, leaky bowel, endotoxin, bile acids enterohepatic circulation, metabolites, or alcohol-producing microbiota, are involved. Currently, diagnosis and treatment techniques using these mechanisms are being developed. In this review, we will introduce the microbiota-related mechanisms in the progression of NAFLD and future directions will be discussed.
    Keywords:  dysbiosis; gut microbial metabolites; gut microbiota; nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/cells10102634
  5. Front Immunol. 2021 ;12 747794
    Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice.
    Jasmine George, Yuanyuan Zhang, Jacob Sloan, Joya M Sims, John D Imig, Xueying Zhao.
      Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
    Keywords:  Tim-1; high-fat diet; inflammation; lipid metabolism; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.3389/fimmu.2021.747794
  6. Metabolism. 2021 Oct 14. pii: S0026-0495(21)00214-6. [Epub ahead of print] 154914
    C-C chemokine ligand 3 deficiency ameliorates diet-induced Steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice.
    Liang Xu, Yongping Chen, Mayumi Nagashimada, Yinhua Ni, Fen Zhuge, Guanliang Chen, Haoran Li, Tongtong Pan, Tatsuya Yamashita, Naofumi Mukaida, Shuichi Kaneko, Tsuguhito Ota, Naoto Nagata.
       BACKGROUND AND AIMS: The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines and their receptors have potential as therapeutic targets of NAFLD. We investigated the role of CC chemokine ligand 3 (CCL3) in the development of murine and human NAFLD.
    METHODS: CCL3-knockout mice (CCL3-/-) and littermate CCL3 wild-type control mice (WT) were fed a high-cholesterol and high-fat (CL) diet for 16 weeks to induce NAFLD. We investigated the impact of CCL3 gene deletion in bone marrow cells and leptin-deficient ob/ob mice on CL diet-induced steatohepatitis. We assayed the serum CCL3 levels in 36 patients with biopsy-proven NAFLD and nine healthy control subjects.
    RESULTS: Compared with normal chow (NC), the CL diet induced steatohepatitis and hepatic fibrosis and elevated the plasma CCL3 level. In the liver, CCL3 protein colocalized with F4/80+ macrophages, especially CD11c+ M1-like macrophages, rather than other cell types. CCL3-/- attenuated CL diet-induced steatohepatitis and fibrosis associated with M2-dominant liver macrophages compared with the WT. The reconstitution of bone marrow (BM) cells from CCL3-/- attenuated steatohepatitis in WT mice fed a CL diet. Furthermore, crossing CCL3-/- onto the ob/ob background prevented CL diet-induced NAFLD in ob/ob mice, which was associated with a lesser inflammatory phenotype of liver macrophages. Also, the serum and hepatic levels of CCL3 were significantly increased in patients with non-alcoholic steatohepatitis (NASH) compared to those with simple fatty liver (NAFL) and healthy subjects.
    CONCLUSION: Our data indicate that CCL3 facilitates macrophage infiltration into the liver and M1 polarization in the progression of steatohepatitis and highlight the need for further studies to determine the effect of CCL3-CCR1 and -CCR5 signaling blockade on the treatment of NAFLD.
    Keywords:  CC chemokine ligand 3; Fibrosis; Inflammation; Macrophage polarization; NAFLD
    DOI:  https://doi.org/10.1016/j.metabol.2021.154914
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