Editors' ChoiceMetabolism

The Pathway to Dyslipidemia

Science's STKE  01 Feb 2005:
Vol. 2005, Issue 269, pp. tw42
DOI: 10.1126/stke.2692005tw42

There is no doubt that a diet high in saturated fats causes changes in lipid metabolism that can lead to atherosclerosis. However, the mechanisms by which this process is controlled are not well understood. Therefore, Lin et al. set out to characterize changes in gene expression in mice fed on a diet rich in saturated fats. Gene expression arrays revealed that the expression of key regulators of lipid metabolism in the liver was increased. One such factor was SREBP (sterol regulatory element-binding protein), and another was the transcriptional coactivator PGC-1β. In transfected hepatoma cells, the authors showed that PGC-1β enhanced expression of SREBP-responsive genes. PGC-1β was also detected by chromatin immunoprecipitation on promoters of endogenous SREBP target genes. Adenoviral expression of PGC-1β in rat liver stimulated expression of numerous genes involved in regulation of lipid metabolism. SREBP appeared to be necessary for these effects, because a dominant negative mutant of SREBP reduced such effects of PGC-1β. The physiological effects of PGC-1β are similar to those of liver-X receptor, and PGC-1β enhanced ligand-dependent expression of a reporter gene with LXR binding sites. In cultured cells, RNAi to PGC-1β reduced the expression of genes regulating lipogenesis. In vivo administration of RNAi to PGC-1β to mice decreased the expression of key lipogenic enzymes in the liver in mice fed on a high-fat diet. Thus, increased expression of PGC-1β appears to be an important event in mediating the effects of a high-fat diet on lipid metabolism. The authors note that PGC-1β is therefore a potentially effective therapeutic target to reduce the deadly effects of overindulgence in dietary saturated fats.

J. Lin, R. Yang, P. T. Tarr, P.-H. Wu, C. Handschin, S. Li, W. Yang, L. Pei, M. Uldry, P. Tontonoz, C. B. Newgard, B. M. Spiegelman, Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 120, 261-273 (2005). [PubMed]