Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities

Arun J. Sanyal, Carol Campbell-Sargent, Faridoddin Mirshahi, William B. Rizzo, Melissa J. Contos, Richard K. Sterling, Velimir A. Luketic, Mitchell L. Shiffman, John N. Clore

Research output: Contribution to journalArticle

1474 Citations (Scopus)

Abstract

Background and Aims: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid β oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. Methods: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU · m-2 · min-1) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-13C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid β oxidation from serum [β-OH butyrate], release of water-soluble radioactivity from 3H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). Results: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 μmol · kg-1 · min-1; P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU · m-2 · min-1. NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid β oxidation was noted in any group. Also, mean [β-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 μmol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. Conclusions: These data indicate that peripheral insulin resistance, increased fatty acid β oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.

Original languageEnglish (US)
Pages (from-to)1183-1192
Number of pages10
JournalGastroenterology
Volume120
Issue number5
DOIs
StatePublished - Apr 2001

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Insulin Resistance
Fatty Liver
Fatty Acids
Glycerol
Oxidative Stress
Butyrates
Lipolysis
Liver
Staining and Labeling
Vascular Resistance
Non-alcoholic Fatty Liver Disease
Hepatocytes
Insulin
Dicarboxylic Acids
Glucose Clamp Technique
Palmitates
Nonesterified Fatty Acids
Radioactivity
Lipid Peroxidation
Mitochondria

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., ... Clore, J. N. (2001). Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology, 120(5), 1183-1192. https://doi.org/10.1053/gast.2001.23256

Nonalcoholic steatohepatitis : Association of insulin resistance and mitochondrial abnormalities. / Sanyal, Arun J.; Campbell-Sargent, Carol; Mirshahi, Faridoddin; Rizzo, William B.; Contos, Melissa J.; Sterling, Richard K.; Luketic, Velimir A.; Shiffman, Mitchell L.; Clore, John N.

In: Gastroenterology, Vol. 120, No. 5, 04.2001, p. 1183-1192.

Research output: Contribution to journalArticle

Sanyal, AJ, Campbell-Sargent, C, Mirshahi, F, Rizzo, WB, Contos, MJ, Sterling, RK, Luketic, VA, Shiffman, ML & Clore, JN 2001, 'Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities', Gastroenterology, vol. 120, no. 5, pp. 1183-1192. https://doi.org/10.1053/gast.2001.23256
Sanyal, Arun J. ; Campbell-Sargent, Carol ; Mirshahi, Faridoddin ; Rizzo, William B. ; Contos, Melissa J. ; Sterling, Richard K. ; Luketic, Velimir A. ; Shiffman, Mitchell L. ; Clore, John N. / Nonalcoholic steatohepatitis : Association of insulin resistance and mitochondrial abnormalities. In: Gastroenterology. 2001 ; Vol. 120, No. 5. pp. 1183-1192.
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T2 - Association of insulin resistance and mitochondrial abnormalities

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AU - Campbell-Sargent, Carol

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AU - Rizzo, William B.

AU - Contos, Melissa J.

AU - Sterling, Richard K.

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N2 - Background and Aims: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid β oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. Methods: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU · m-2 · min-1) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-13C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid β oxidation from serum [β-OH butyrate], release of water-soluble radioactivity from 3H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). Results: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 μmol · kg-1 · min-1; P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU · m-2 · min-1. NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid β oxidation was noted in any group. Also, mean [β-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 μmol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. Conclusions: These data indicate that peripheral insulin resistance, increased fatty acid β oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.

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