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High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes

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Abstract

An imbalance in the redox state, increased levels of lipid precursors and overactivation of de novo lipogenesis determine the development of fibrosis during nonalcoholic steatohepatitis (NASH). We evaluated the modulation of NADPH-producing enzymes associated with the antifibrotic, antioxidant and antilipemic effects of nicotinamide (NAM) in a model of NASH induced by excess fructose consumption. Male rats were provided drinking water containing 40% fructose for 16 weeks. During the last 12 weeks of fructose administration, water containing NAM was provided to some of the rats for 5 h/day. The biochemical profiles and the ghrelin, leptin, lipoperoxidation and TNF-α levels in serum and the glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and NADP+-dependent isocitric dehydrogenase (IDP) levels, the reduced/oxidized glutathione (GSH/GSSG) and reduced/oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H/NAD(P)+) ratios, and the levels of various lipogenic and fibrotic markers in the liver were evaluated. The results showed that hepatic fibrosis induced by fructose consumption was associated with weight gain, hunger-satiety system dysregulation, hyperinsulinemia, dyslipidemia, lipoperoxidation and inflammation. Moreover, increased levels of hepatic G6PD and ME activity and expression, the NAD(P)H/NAD(P)+ ratios, and GSSG concentration and increased expression of lipogenic and fibrotic markers were detected, and these alterations were attenuated by NAM administration. Specifically, NAM diminished the activity and expression of G6PD and ME, and this effect was associated with a decrease in the NADPH/NADP+ ratios, increased GSH levels and decreased lipoperoxidation and inflammation, ameliorating fibrosis and NASH development. NAM reduces liver steatosis and fibrosis by regulating redox homeostasis through a G6PD- and ME-dependent mechanism.

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Acknowledgements

The authors gratefully acknowledge the assistance provided by Dra. Mariela Sánchez Claudio. This research study was funded by Fomento de Investigación en Salud, Instituto Mexicano del Seguro Social (FIS/IMSS/PROT/G15/1424 and FIS/IMSS/PROT/MD/17/1685) and CONACYT (Scholarship 262758).

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Authors and Affiliations

  1. Posgrado en Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico

    S. S. Loza-Medrano

  2. Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), “Bernardo Sepúlveda” Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico

    S. S. Loza-Medrano, R. García-Macedo, O. A. Martínez-Mar, M. C. Sánchez-Becerra, M. Cruz-López & M. Díaz-Flores

  3. Laboratorio en Biología del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, Mexico

    L. A. Baiza-Gutman

  4. Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades “Bernardo Sepúlveda” Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, Mexico

    L. Manuel-Apolinar & L. Damasio-Santana

  5. Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico

    M. A. Ibáñez-Hernández

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  1. S. S. Loza-Medrano
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Loza-Medrano, S.S., Baiza-Gutman, L.A., Manuel-Apolinar, L. et al. High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes. Mol Biol Rep 47, 337–351 (2020). https://doi.org/10.1007/s11033-019-05136-4

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