The temporal relationship of hepatic steatosis and changes in liver oxidative stress and fatty acid (FA) composition to the development of non-alcoholic steatohepatitis (NASH) remain to be clearly defined. Recently, we developed an experimental model of hepatic steatosis and NASH, the transgenic spontaneously hypertensive rat (SHR) that overexpresses a dominant positive form of the human SREBP-1a isoform in the liver. These rats are genetically predisposed to hepatic steatosis at a young age that ultimately progresses to NASH in older animals. Young transgenic SHR versus SHR controls exhibited simple hepatic steatosis which was associated with significantly increased hepatic levels of oxidative stress markers, conjugated dienes, and TBARS, with decreased levels of antioxidative enzymes and glutathione and lower concentrations of plasma alpha- and gamma-tocopherol. Transgenic rats exhibited increased plasma levels of saturated FA, decreased levels of n-3 and n-6 polyunsaturated FA (PUFA), and increased n-6/n-3 PUFA ratios. These results are consistent with the hypothesis that excess fat accumulation in the liver in association with increased oxidative stress and disturbances in the metabolism of saturated and unsaturated fatty acids may precede and contribute to the primary pathogenesis of NASH.

Institute for Clinical and Experimental Medicine Prague Czech Republic

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World J Gastroenterol. 2008 Jan 14;14(2):185-92 PubMed

Clin Chim Acta. 2005 May;355(1-2):105-11 PubMed

Pediatr Res. 2005 Mar;57(3):445-52 PubMed

J Biol Chem. 1957 May;226(1):497-509 PubMed

J Nutr Biochem. 2008 Sep;19(9):567-76 PubMed

Hepatology. 1990 Nov;12(5):1106-10 PubMed

Obesity (Silver Spring). 2007 Jan;15(1):24-31 PubMed

J Investig Med. 2004 Dec;52(8):506-14 PubMed

Diabetologia. 2008 Feb;51(2):328-35 PubMed

Trends Mol Med. 2006 Dec;12(12):555-8 PubMed

Vet Pathol. 1998 May;35(3):227-9 PubMed

J Clin Invest. 1985 Aug;76(2):517-27 PubMed

J Nutr. 2000 Jun;130(6):1561-5 PubMed

World J Gastroenterol. 2008 Apr 28;14(16):2474-86 PubMed

J Hepatol. 2008 Feb;48(2):300-7 PubMed

Int J Clin Pract. 2005 Mar;59(3):318-23 PubMed

Biochimie. 2004 Nov;86(11):799-806 PubMed

Gastroenterology. 1998 Apr;114(4):842-5 PubMed

Ann N Y Acad Sci. 2002 Jun;967:446-53 PubMed

Hypertension. 2005 May;45(5):1004-11 PubMed

Lipids. 2003 Jul;38(7):733-42 PubMed

Anal Biochem. 1968 Oct 24;25(1):192-205 PubMed

Clin Sci (Lond). 2004 Jun;106(6):635-43 PubMed

Liver Int. 2005 Oct;25(5):946-53 PubMed

J Lab Clin Med. 1976 Jun;87(6):1057-64 PubMed

J Nutr. 2005 Nov;135(11):2634-8 PubMed

J Clin Invest. 1988 Mar;81(3):720-9 PubMed

Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):327-35 PubMed

J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S5-10 PubMed

J Nutr Sci Vitaminol (Tokyo). 2001 Apr;47(2):102-7 PubMed

Methods Enzymol. 1986;123:215-9 PubMed

Methods Enzymol. 1984;105:121-6 PubMed

Am J Clin Nutr. 2006 Dec;84(6):1290-8 PubMed

Ann Clin Lab Sci. 2004 Winter;34(1):57-62 PubMed

Clin Sci (Lond). 2004 Mar;106(3):261-8 PubMed

Ann N Y Acad Sci. 2002 Jun;967:183-95 PubMed

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