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Exploring the signal-dependent transcriptional regulation involved in the liver pathology of type 2 diabetes

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Abstract

Excess glucagon activity in diabetes increases hepatic glucose production via gluconeogenic gene induction, thus exacerbating hyperglycemia. Glucagon receptor-activated cAMP-dependent protein kinase A (PKA) induces proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression via the cAMP response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) pathway. Transcriptional coactivator PGC-1α subsequently coactivates transcription factors, such as forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4 alpha (HNF4α), to induce gluconeogenic genes. The current review first summarizes the mechanism by which transcriptional cofactor CBP and p300-activated transactivator with glutamic acid and aspartic acid-rich COOH-terminal domain 2 (CITED2) activates gluconeogenesis via the regulation of PGC-1α and general control of amino acid synthesis protein 5-like 2 (GCN5). Type 2 diabetes is closely linked with non-alcoholic fatty liver disease (NAFLD). Between 10 and 20% of NAFLD progresses to non-alcoholic steatohepatitis (NASH), which can cause liver cirrhosis and can also lead to hepatocellular carcinoma. Liver macrophages are considered to be related to inflammation and fibrosis observed in NASH. This review outlines liver-derived signals underlying the differentiation of liver macrophages and the mechanism of myeloid cell diversification in NASH.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this review.

References

  1. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.

    Article  CAS  Google Scholar 

  2. Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol. 2006;68:123–58.

    Article  CAS  Google Scholar 

  3. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801.

    Article  Google Scholar 

  4. Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 2011;14(1):9–19.

    Article  CAS  Google Scholar 

  5. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1(6):361–70.

    Article  Google Scholar 

  6. Altarejos JY, Montminy M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12(3):141–51.

    Article  CAS  Google Scholar 

  7. Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A, Puigserver P. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 2006;3(6):429–38.

    Article  CAS  Google Scholar 

  8. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005;280(16):16456–60.

    Article  CAS  Google Scholar 

  9. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8.

    Article  CAS  Google Scholar 

  10. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, et al. Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA. 2003;100(7):4012–7.

    Article  CAS  Google Scholar 

  11. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423(6939):550–5.

    Article  CAS  Google Scholar 

  12. Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 1999;13(1):64–75.

    Article  CAS  Google Scholar 

  13. Qu X, Lam E, Doughman YQ, Chen Y, Chou YT, Lam M, et al. Cited2, a coactivator of HNF4alpha, is essential for liver development. EMBO J. 2007;26(21):4445–56.

    Article  CAS  Google Scholar 

  14. Sakai M, Matsumoto M, Tujimura T, Yongheng C, Noguchi T, Inagaki K, et al. CITED2 links hormonal signaling to PGC-1alpha acetylation in the regulation of gluconeogenesis. Nat Med. 2012;18(4):612–7.

    Article  CAS  Google Scholar 

  15. Kuo MH, Zhou J, Jambeck P, Churchill ME, Allis CD. Histone acetyltransferase activity of yeast Gcn5p is required for the activation of target genes in vivo. Genes Dev. 1998;12(5):627–39.

    Article  CAS  Google Scholar 

  16. Sakai M, Tujimura-Hayakawa T, Yagi T, Yano H, Mitsushima M, Unoki-Kubota H, et al. The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nat Commun. 2016;7:13147.

    Article  CAS  Google Scholar 

  17. Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018;67(4):1270–83.

    Article  CAS  Google Scholar 

  18. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115(1):56–65.

    Article  CAS  Google Scholar 

  19. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159(6):1312–26.

    Article  CAS  Google Scholar 

  20. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159(6):1327–40.

    Article  CAS  Google Scholar 

  21. Hoeksema MA, Glass CK. Nature and nurture of tissue-specific macrophage phenotypes. Atherosclerosis. 2019;281:159–67.

    Article  CAS  Google Scholar 

  22. Haldar M, Kohyama M, So AY, Kc W, Wu X, Briseno CG, et al. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell. 2014;156(6):1223–34.

    Article  CAS  Google Scholar 

  23. Okabe Y, Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014;157(4):832–44.

    Article  CAS  Google Scholar 

  24. Ginhoux F, Guilliams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity. 2016;44(3):439–49.

    Article  CAS  Google Scholar 

  25. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.

    Article  CAS  Google Scholar 

  26. Bleriot C, Dupuis T, Jouvion G, Eberl G, Disson O, Lecuit M. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity. 2015;42(1):145–58.

    Article  CAS  Google Scholar 

  27. Seidman JS, Troutman TD, Sakai M, Gola A, Spann NJ, Bennett H, et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity. 2020;52(6):1057-74.e7.

    Article  CAS  Google Scholar 

  28. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.

    Article  CAS  Google Scholar 

  29. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, et al. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity. 2019;51(4):655-70.e8.

    Article  CAS  Google Scholar 

  30. Bonnardel J, T’Jonck W, Gaublomme D, Browaeys R, Scott CL, Martens L, et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity. 2019;51(4):638-54.e9.

    Article  CAS  Google Scholar 

  31. Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gelineau A, et al. Impaired Kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis. Immunity. 2020;53(3):627-40.e5.

    Article  CAS  Google Scholar 

  32. Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, et al. Lipid-associated macrophages control metabolic homeostasis in a trem2-dependent manner. Cell. 2019;178(3):686-98.e14.

    Article  CAS  Google Scholar 

  33. Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019;575(7783):512–8.

    Article  CAS  Google Scholar 

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Acknowledgements

A summary of this review was presented in the Lilly Award Lecture at the 65th Annual Meeting of the Japan Diabetes Society, Kobe, Japan. I would like to express sincere gratitude to Dr. Michihiro Matsumoto (National Center for Global Health and Medicine), Dr. Masato Kasuga (The Institute for Medical Science, Asahi Life Foundation), and Professor Christopher K. Glass (University of California San Diego) for their mentoring and to my colleagues and collaborators for their support. The author was supported by JSPS KAKENHI (26713033), the Manpei Suzuki Diabetes Foundation of Tokyo, Japan, and the Osamu Hayaishi Memorial Scholarship for Study Abroad, Japan. Figures contain icons from Biorender.com.

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  1. Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8602, Japan

    Mashito Sakai

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Sakai, M. Exploring the signal-dependent transcriptional regulation involved in the liver pathology of type 2 diabetes. Diabetol Int 14, 15–20 (2023). https://doi.org/10.1007/s13340-022-00610-0

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