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Analysis of Insulin Resistance in Nonalcoholic Steatohepatitis

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Non-Alcoholic Steatohepatitis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2455))

Abstract

Insulin resistance is a major phenotype observed in nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD). Insulin resistance in NASH is characterized by reductions in whole body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying hepatic insulin resistance is primarily associated with hepatic glucose production (HGP) rate. Hepatic insulin resistance can also be a consequence or a driving factor of hepatic lipid accumulation by increasing free fatty acid synthesis, delivery, and catabolism. The common method to assess hepatic insulin resistance is to measure hepatic glucose production (HGP) using isotope tracer distribution technique. However, non-radioactive approaches have been developed to assess hepatic insulin resistance in the context of NASH. In this chapter, we describe the methods to evaluate hepatic insulin resistance in animal models of NASH by examining insulin sensitivity and glucose tolerance as well as the key molecules in hepatic insulin signaling pathways.

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References

  1. Wieckowska A, McCullough AJ, Feldstein AE (2007) Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 46:582–589

    Article  CAS  Google Scholar 

  2. Birkenfeld AL, Shulman GI (2013) Non alcoholic fatty liver disease, hepatic insulin resistance and type 2 diabetes. Hepatology 59:713–723

    Article  Google Scholar 

  3. Utzschneider KM, Kahn SE (2006) Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 91:4753–4761

    Article  CAS  Google Scholar 

  4. Abdul-Ghani MA, Jenkinson CP, Richardson DK et al (2006) Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the veterans administration genetic epidemiology study. Diabetes 55:1430–1435

    Article  CAS  Google Scholar 

  5. Kim H, Zheng Z, Walker PD et al (2017) CREBH maintains circadian glucose homeostasis by regulating hepatic glycogenolysis and gluconeogenesis. Mol Cell Biol 37:e00048-17

    Article  Google Scholar 

  6. Groop LC, Bonadonna RC, DelPrato S et al (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205–213

    Article  CAS  Google Scholar 

  7. Titchenell PM, Chu Q, Monks BR et al (2015) Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat Commun 6:7078

    Article  CAS  Google Scholar 

  8. Matsumoto M, Pocai A, Rossetti L et al (2007) Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab 6:208–216

    Article  CAS  Google Scholar 

  9. Dentin R, Liu Y, Koo SH et al (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449:366–369

    Article  CAS  Google Scholar 

  10. Koo SH, Flechner L, Qi L et al (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437:1109–1111

    Article  CAS  Google Scholar 

  11. Dong XC, Copps KD, Guo S et al (2008) Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8:65–76

    Article  CAS  Google Scholar 

  12. Lu M, Wan M, Leavens KF et al (2012) Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18:388–395

    Article  CAS  Google Scholar 

  13. Draznin B (2006) Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes 55:2392–2397

    Article  CAS  Google Scholar 

  14. Lavin DP, White MF, Brazil DP (2016) IRS proteins and diabetic complications. Diabetologia 59:2280–2291

    Article  CAS  Google Scholar 

  15. Cheng Z, Tseng Y, White MF (2010) Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab 21:589–598

    Article  CAS  Google Scholar 

  16. Lee YH, Giraud J, Davis RJ et al (2003) c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 278:2896–2902

    Article  CAS  Google Scholar 

  17. Copps KD, White MF (2012) Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55:2565–2582

    Article  CAS  Google Scholar 

  18. Copps KD, Hancer NJ, Opare-Ado L et al (2010) Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab 11:84–92

    Article  CAS  Google Scholar 

  19. Morino K, Petersen KF, Dufour S et al (2005) Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115:3587–3593

    Article  CAS  Google Scholar 

  20. Taniguchi CM, Ueki K et al (2016) Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest 126:4387

    Article  Google Scholar 

  21. Dong X, Park S, Lin X et al (2006) Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest 116:101–114

    Article  CAS  Google Scholar 

  22. Kubota N, Kubota T, Kajiwara E et al (2016) Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity. Nat Commun 7:12977

    Article  CAS  Google Scholar 

  23. Samuel VT, Liu ZX, Qu X et al (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–32353

    Article  CAS  Google Scholar 

  24. Matthews DR, Hosker JP, Rudenski AS et al (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  CAS  Google Scholar 

  25. Larter CZ, Yeh MM (2008) Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol 23:1635–1648

    Article  Google Scholar 

  26. Matsuzawa N, Takamura T, Kurita S et al (2007) Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46:1392–1403

    Article  CAS  Google Scholar 

  27. Paigen B, Morrow A, Holmes PA et al (1987) Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68:231–240

    Article  CAS  Google Scholar 

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Acknowledgments

This work was partly supported by National Institutes of Health (NIH) under Grant DK090313 and DK126908 (to K.Z.).

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Authors and Affiliations

  1. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA

    Hyunbae Kim, Zhenfeng Song & Kezhong Zhang

  2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Deqiang Zhang & Xin Tong

  3. Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, USA

    Kezhong Zhang

Authors
  1. Hyunbae Kim
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  2. Deqiang Zhang
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  3. Zhenfeng Song
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  4. Xin Tong
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  5. Kezhong Zhang
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Corresponding authors

Correspondence to Xin Tong or Kezhong Zhang .

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Editors and Affiliations

  1. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Devanand Sarkar

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© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

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Kim, H., Zhang, D., Song, Z., Tong, X., Zhang, K. (2022). Analysis of Insulin Resistance in Nonalcoholic Steatohepatitis. In: Sarkar, D. (eds) Non-Alcoholic Steatohepatitis. Methods in Molecular Biology, vol 2455. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2128-8_18

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  • DOI: https://doi.org/10.1007/978-1-0716-2128-8_18

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2127-1

  • Online ISBN: 978-1-0716-2128-8

  • eBook Packages: Springer Protocols

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