J. Lipid Res.
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A more recent version of this article appeared on September 1, 2006

Papers In Press, published online ahead of print June 21, 2006
J. Lipid Res., doi:10.1194/jlr.M600177-JLR200
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Submitted on April 19, 2006
Revised on June 20, 2006
Accepted on June 20, 2006

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity

Yun Wang, Daniela Botolin, Jinghua Xu, Barbara Christian, Ernestine Mitchell, Bolleddula Jayaprakasam, Muraleedharan Nair, Jeffery Peters, Julia Busik, L. Karl Olson, and Donald B. Jump

Physiology Dept., Michigan State University, East Lansing, MI 48824

Corresponding Author: jump{at}msu.edu

Hepatic fatty acid elongases (Elovl-1, -2, -5 and -6) and desaturases (delta5, delta6 and delta9) play an important role in hepatic and whole body lipid composition. This report examines the role key transcription factors play in the control of hepatic elongase and desaturase expression and lipid composition in rat primary hepatocytes and in liver in vivo. Studies with PPARalpha (-/-) null mice establish that PPARalpha is required for WY14643-mediated induction of Elovl-5, Elovl-6 and all 3 desaturases (delta5D, delta6D and delta9D). Nuclear SREBP-1 was increased in hepatocyte nuclei by insulin, the LXR agonist (T1317) or by recombinant adenoviral over expression. Elevated nuclear SREBP-1 correlated with induction of transcripts encoding Elovl-6, delta5D, delta6D and delta9D. Of these, only delta9D is also regulated independently by LXR agonist. Glucose induction of L-pyruvate kinase (L-PK), delta9D and Elovl-6 expression correlated with the accumulation of ChREBP in nuclei of rat primary hepatocytes. Over expression of dominant negative MLX established that the ChREBP/MLX heterodimer was required for glucose induction of these transcripts. Suppression of Elovl-6 and delta9D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose intolerant mice correlated with low levels of nuclear SREBP-1. In leptin deficient obese mice (Lepob/ob), elevated SREBP-1 and MLX nuclear content correlated with elevated Elovl-5, Elovl-6 and delta9D expression and massive accumulation of monounsaturated fatty acids (18:1,n-7 & n-9) in hepatic neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression and elongase enzyme activity. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP and MLX in the control of hepatic fatty acid elongase and desaturase expression and hepatic lipid composition.


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