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      Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems

      research-article
      Author(s): 1 , 1 , 1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 , 5 , 4 , 4 , 1 , 1 , 1 , ∗
      Publication date (Electronic):
      Journal: Cellular and Molecular Gastroenterology and Hepatology
      Publisher: Elsevier
      Keywords: Fatty Liver Disease, NASH, Lipogenesis, Fibrosis, Acetyl-CoA Carboxylase, ACC, acetyl-CoA carboxylase, ALT, alanine aminotransferase, αSMA, α-smooth muscle actin, AST, aspartate aminotransferase, ATP, adenosine triphosphate, CD3, cluster of differentiation 3, CDAHFD, choline-deficient and high-fat diet, DAB, 3,3′-diaminobenzidine, DEN, diethylnitrosamine, DMSO, dimethyl sulfoxide, DNL, de novo lipogenesis, EC50, median effective concentration, hACC, human ACC, HSC, primary hepatic stellate cell, IC50, median inhibitory concentration, IHC, immunohistochemistry, IL, interleukin, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, PSR, Picro Sirius red, SWE, shear wave elastography, TG, triglyceride, TGFβ1, transforming growth factor β1, TH17 cells, inflammatory interleukin 17 secreting T cells of the T helper 17 lineage, Treg cells, anti-inflammatory Foxp3(+) regulatory T cells, VLDL, very-low-density lipoprotein

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          Abstract

          Background & Aims

          Disordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in de novo lipogenesis (DNL) and modulates mitochondrial fatty acid oxidation. Increased hepatic DNL flux and reduced fatty acid oxidation are hypothesized to contribute to steatosis. Some proinflammatory cells also show increased dependency on DNL, suggesting that ACC may regulate aspects of the inflammatory response in NASH. PF-05221304 is an orally bioavailable, liver-directed ACC1/2 inhibitor. The present studies sought to evaluate the effects of PF-05221304 on NASH pathogenic factors in experimental model systems.

          Methods

          The effects of PF-05221304 on lipid metabolism, steatosis, inflammation, and fibrogenesis were investigated in both primary human-derived in vitro systems and in vivo rodent models.

          Results

          PF-05221304 inhibited DNL, stimulated fatty acid oxidation, and reduced triglyceride accumulation in primary human hepatocytes, and reduced DNL and steatosis in Western diet–fed rats in vivo, showing the potential to reduce hepatic lipid accumulation and potentially lipotoxicity. PF-05221304 blocked polarization of human T cells to proinflammatory but not anti-inflammatory T cells, and suppressed activation of primary human stellate cells to myofibroblasts in vitro, showing direct effects on inflammation and fibrogenesis. Consistent with these observations, PF-05221304 also reduced markers of inflammation and fibrosis in the diethylnitrosamine chemical–induced liver injury model and the choline-deficient, high-fat–fed rat model.

          Conclusions

          The liver-directed dual ACC1/ACC2 inhibitor directly improved multiple nonalcoholic fatty liver disease/NASH pathogenic factors including steatosis, inflammation, and fibrosis in both human-derived in vitro systems and rat models.

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          Fueling immunity: insights into metabolism and lymphocyte function.

          Erika L Pearce, Maya Poffenberger, Chih-Hao Chang … (2013)
          Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function.
          Article 0 comments Cited 578 times – based on 0 reviews     Review now
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            De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.

            Luciana Berod, Christin Friedrich, Amrita Nandan … (2014)
            Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.
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              Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver.

              Monika Rau, Anne-Kristin Schilling, Jan Meertens … (2016)
              Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-γ(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.
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                Author and article information

                Contributors
                William P. Esler
                Journal
                Journal ID (nlm-ta): Cell Mol Gastroenterol Hepatol
                Journal ID (iso-abbrev): Cell Mol Gastroenterol Hepatol
                Title: Cellular and Molecular Gastroenterology and Hepatology
                Publisher: Elsevier
                ISSN (Electronic): 2352-345X
                Publication date Collection: 2020
                Publication date (Electronic): 09 June 2020
                Volume: 10
                Issue: 4
                Pages: 829-851
                Affiliations
                [1 ]Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge Massachusetts
                [2 ]Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge Massachusetts
                [3 ]Early Clinical Development, Pfizer Worldwide Research and Development, Cambridge Massachusetts
                [4 ]Drug Safety Research and Development, Pfizer Worldwide Research and Development, Cambridge Massachusetts
                [5 ]Comparative Medicine, Pfizer Worldwide Research and Development, Cambridge Massachusetts
                Author notes
                [∗ ] Correspondence Address correspondence to: William P. Esler, PhD, Internal Medicine Research Unit, Pfizer, Inc, 1 Portland Street, Cambridge, Massachusetts 02139. William.Esler@ 123456Pfizer.com
                Article
                Publisher ID: S2352-345X(20)30090-4
                DOI: 10.1016/j.jcmgh.2020.06.001
                PMC ID: 7509217
                PubMed ID: 32526482
                SO-VID: 9fcf0bc2-7149-4570-8f78-d7a2fe456783
                Copyright © © 2020 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 November 2019
                Date accepted : 2 June 2020
                Categories
                Subject: Original Research

                Keywords: fatty liver disease,nash,lipogenesis,fibrosis,acetyl-coa carboxylase,acc, acetyl-coa carboxylase,alt, alanine aminotransferase,αsma, α-smooth muscle actin,ast, aspartate aminotransferase,atp, adenosine triphosphate,cd3, cluster of differentiation 3,cdahfd, choline-deficient and high-fat diet,dab, 3,3′-diaminobenzidine,den, diethylnitrosamine,dmso, dimethyl sulfoxide,dnl, de novo lipogenesis,ec50, median effective concentration,hacc, human acc,hsc, primary hepatic stellate cell,ic50, median inhibitory concentration,ihc, immunohistochemistry,il, interleukin,nafld, nonalcoholic fatty liver disease,nash, nonalcoholic steatohepatitis,psr, picro sirius red,swe, shear wave elastography,tg, triglyceride,tgfβ1, transforming growth factor β1,th17 cells, inflammatory interleukin 17 secreting t cells of the t helper 17 lineage,treg cells, anti-inflammatory foxp3(+) regulatory t cells,vldl, very-low-density lipoprotein
                Data availability:
                Keywords: fatty liver disease, nash, lipogenesis, fibrosis, acetyl-coa carboxylase, acc, acetyl-coa carboxylase, alt, alanine aminotransferase, αsma, α-smooth muscle actin, ast, aspartate aminotransferase, atp, adenosine triphosphate, cd3, cluster of differentiation 3, cdahfd, choline-deficient and high-fat diet, dab, 3,3′-diaminobenzidine, den, diethylnitrosamine, dmso, dimethyl sulfoxide, dnl, de novo lipogenesis, ec50, median effective concentration, hacc, human acc, hsc, primary hepatic stellate cell, ic50, median inhibitory concentration, ihc, immunohistochemistry, il, interleukin, nafld, nonalcoholic fatty liver disease, nash, nonalcoholic steatohepatitis, psr, picro sirius red, swe, shear wave elastography, tg, triglyceride, tgfβ1, transforming growth factor β1, th17 cells, inflammatory interleukin 17 secreting t cells of the t helper 17 lineage, treg cells, anti-inflammatory foxp3(+) regulatory t cells, vldl, very-low-density lipoprotein

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