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NAFLD

Metabolic make-up of NASH: from fat and sugar to amino acids

Nature Reviews Gastroenterology & Hepatology volume 11, pages 205–207 (2014)Cite this article

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NAFLD is regarded unquestionably as one of the components of the metabolic syndrome. Hence, metabolic perturbations occurring in the fatty liver become a systemic metabolic derangement. The phenotypic switching from fatty liver to NASH entails a reprogramming of liver metabolism to fit a stressful metabolic environment.

The new findings1 suggest that NASH might be associated with elevated blood concentrations of chondroitin sulphate. This finding is perhaps not surprising because chondroitin sulphate modulates the cellular processes involved in inflammation, including cytokine and growth factor activities, and is a component of the extracellular matrix, which is increased in fibrosis. Notably, a genome-wide association study (GWAS) of patients with NAFLD showed that a gene variant near the NCAN locus (neurocan core protein) was associated with NASH.2 Moreover, Mardinoglu et al.1 predicted that there is an imbalance in amino acid metabolism that brings new players in the pathogenesis of NASH to our attention. Consequently, we should now consider blood levels of fat and sugar, and the levels of branched-chain amino acids (BCAAs) and metabolites of the glutamine-cycling pathway in NASH pathogenesis.3 Although this metabolic signature has been reported in related clinical conditions, such as obesity,3 type 2 diabetes mellitus,4 and cardiovascular disease,5 these findings reinforce the concept of the potential application of metabolic biomarkers in the clinical setting. The main hypothesis behind these observations is that the increase in BCAAs in NAFLD is associated with perpetuation of the insulin resistance phenotype as these amino acids are primarily gluconeogenic. Taken together, these observations emphasize that NAFLD is not a bystander condition associated with the metabolic syndrome, but is critically involved in its development.6 Perhaps we can now suppose that all the global metabolic derangements of the metabolic syndrome start in the fatty liver?

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Figure 1: Proposed hypothesis regarding metabolic changes associated with NAFLD progression and the prediction of protein–chemical interactions based on metabolic modelling.

References

  1. Mardinoglu, A. et al. Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 3083 (2014).

    Article  Google Scholar 

  2. Speliotes, E.K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).

    Article  CAS  Google Scholar 

  3. Newgard, C.B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

    Article  CAS  Google Scholar 

  4. Wang, T.J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  Google Scholar 

  5. Shah, S.H. et al. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ. Cardiovasc. Genet. 3, 207–214 (2010).

    Article  CAS  Google Scholar 

  6. Sookoian, S. et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1α promoter. Hepatology 52, 1992–2000 (2010).

    Article  CAS  Google Scholar 

  7. Pirola, C.J. et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62, 1356–1363 (2013).

    Article  CAS  Google Scholar 

  8. Sanyal, A.J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).

    Article  CAS  Google Scholar 

  9. Sookoian, S. & Pirola, C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53, 1883–1894 (2011).

    Article  CAS  Google Scholar 

  10. Anstee, Q.M. & Day, C. P. The genetics of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 645–655 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are partially supported by grants PICT 2010-0441 and PICT 2012-159 (Agencia Nacional de Promoción Científica y Tecnológica), and UBACYT CM04 (Universidad de Buenos Aires). S.S. and C.J.P. belong to Consejo Nacional de Investigaciones Científicas (CONICET).

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  1. Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires–National Scientific and Technical Research Council (CONICET), Combatiente de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina

    Silvia Sookoian

  2. Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires–National Scientific and Technical Research Council (CONICET), Combatiente de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina

    Carlos J. Pirola

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Correspondence to Silvia Sookoian.

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Sookoian, S., Pirola, C. Metabolic make-up of NASH: from fat and sugar to amino acids. Nat Rev Gastroenterol Hepatol 11, 205–207 (2014). https://doi.org/10.1038/nrgastro.2014.25

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