TY - JOUR
T1 - Metabolic factors in the development of hepatic steatosis and altered mitochondrial gene expression in vivo
AU - Wang, Shaoyun
AU - Kamat, Amrita
AU - Pergola, Pablo
AU - Swamy, Anita
AU - Tio, Fermin
AU - Cusi, Kenneth
N1 - Funding Information:
We would like to thank Sergio Garcia for his assistance with the animal work. The project described was supported by the Burroughs Wellcome Fund, the American Diabetes Association, and the Veterans Affairs Medical Research Fund (Kenneth Cusi); by a Grant in Aid Award from the American Heart Association, South Central Affiliate (Pablo Pergola, MD, and Amrita Kamat, PhD); and by Award Number UL 1RR025767 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources of the National Institutes of Health.
PY - 2011/8
Y1 - 2011/8
N2 - The objective of the study was to understand the role in vivo of elevated plasma free fatty acids (FFA), insulin, and glucose levels in the development of steatosis and altered mitochondrial gene/protein expression. We studied 4 groups of Sprague-Dawley rats: (1) high-fat diet (HFD), (2) high-dose streptozotocin-induced diabetes (T1DM), (3) low-dose streptozotocin-induced diabetic rats on an HFD (T2DM), and (4) controls. Liver histology and expression of genes/proteins related to mitochondrial fatty acid oxidation and biogenesis were analyzed. Despite an attempt to compensate by increasing expression of genes of fatty acid oxidation (carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase), the HFD and diabetic groups developed marked steatosis and suffered a significant reduction in mitochondrial biogenesis gene expression (nuclear respiratory factor 1/transcriptional factor A, mitochondrial). In T2DM rats, the combination of high glucose and FFA unexpectedly did not lead to greater fat accumulation than HFD alone. Greater steatosis in HFD vs T2DM (P <.001) correlated with impairment in the gene expression of PPAR-α (ie, fatty acid oxidation) and PGC1α, a major coactivator for mitochondrial biogenesis. Steatosis was not severe in insulin-deficient T1DM rats despite very elevated FFA and glucose levels. Increased carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase/PPAR-α gene expression suggested inadequate adaptation to high FFA in both T1DM/T2DM rats. Hyperinsulinemia combined with elevated FFA is the key metabolic factor driving hepatic lipogenesis in vivo (HFD rats). Mitochondrial biogenesis (nuclear respiratory factor 1; transcriptional factor A, mitochondrial) is highly susceptible to FFA-induced steatosis. In contrast, hyperglycemia does not have an additive effect (T2DM) and leads to only a modest degree of steatosis in the absence of hyperinsulinemia, even when FFA are extremely elevated as in T1DM rats.
AB - The objective of the study was to understand the role in vivo of elevated plasma free fatty acids (FFA), insulin, and glucose levels in the development of steatosis and altered mitochondrial gene/protein expression. We studied 4 groups of Sprague-Dawley rats: (1) high-fat diet (HFD), (2) high-dose streptozotocin-induced diabetes (T1DM), (3) low-dose streptozotocin-induced diabetic rats on an HFD (T2DM), and (4) controls. Liver histology and expression of genes/proteins related to mitochondrial fatty acid oxidation and biogenesis were analyzed. Despite an attempt to compensate by increasing expression of genes of fatty acid oxidation (carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase), the HFD and diabetic groups developed marked steatosis and suffered a significant reduction in mitochondrial biogenesis gene expression (nuclear respiratory factor 1/transcriptional factor A, mitochondrial). In T2DM rats, the combination of high glucose and FFA unexpectedly did not lead to greater fat accumulation than HFD alone. Greater steatosis in HFD vs T2DM (P <.001) correlated with impairment in the gene expression of PPAR-α (ie, fatty acid oxidation) and PGC1α, a major coactivator for mitochondrial biogenesis. Steatosis was not severe in insulin-deficient T1DM rats despite very elevated FFA and glucose levels. Increased carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase/PPAR-α gene expression suggested inadequate adaptation to high FFA in both T1DM/T2DM rats. Hyperinsulinemia combined with elevated FFA is the key metabolic factor driving hepatic lipogenesis in vivo (HFD rats). Mitochondrial biogenesis (nuclear respiratory factor 1; transcriptional factor A, mitochondrial) is highly susceptible to FFA-induced steatosis. In contrast, hyperglycemia does not have an additive effect (T2DM) and leads to only a modest degree of steatosis in the absence of hyperinsulinemia, even when FFA are extremely elevated as in T1DM rats.
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U2 - 10.1016/j.metabol.2010.12.001
DO - 10.1016/j.metabol.2010.12.001
M3 - Article
C2 - 21310443
AN - SCOPUS:79960555502
SN - 0026-0495
VL - 60
SP - 1090
EP - 1099
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
IS - 8
ER -