Insig(ht)s into Metabolic Control

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Science  19 Aug 2005:
Vol. 309, Issue 5738, pp. 1155
DOI: 10.1126/science.309.5738.1155d

Cholesterol has received a lot of bad press, but it is essential for human health. When we don't get enough cholesterol from our diet, our bodies—specifically our liver—begin to synthesize it. Conversely, when we eat lots of high- cholesterol foods, this biosynthetic machinery shuts down. How this feedback regulation works has fascinated scientists for over 70 years, and in the past decade, considerable progress has been made toward answering that question at the molecular level.

Among the potentially important metabolic regulators identified in studies of cultured cells are the membrane proteins Insigs-1 and -2, so named because they are encoded by insulin-induced genes. The Insigs reside in the endoplasmic reticulum, and they appear to act in part by trapping within this compartment a transcription factor that is required in the nucleus to turn on the expression of genes involved in cholesterol biosynthesis. Engelking et al. show that mice with liver- specific deletions of the Insig genes display a severely blunted feedback response; that is, they continue making cholesterol even when fed a high-cholesterol diet. These results establish the physiological significance of the Insigs in a whole-animal setting and highlight the importance of the liver as the site where the cholesterol feedback system operates. — PAK

J. Clin. Invest. 10.1172/JCI25614 (2005).

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