Targeted Mutation of the MLN64 START Domain Causes only Modest Alterations in Cellular Sterol Metabolism


Por: Kishida T., Kostetskii I., Zhang Z., Martinez F., Liu P., Walkley S.U., Dwyer N.K., Blanchette-Mackie E.J., Radice G.L., Strauss III J.F.

Publicada: 1 ene 2004
Resumen:
The StAR-related lipid transfer (START) domain, first identified in the steroidogenic acute regulatory protein (StAR), is involved in the intracellular trafficking of lipids. Sixteen mammalian START domain-containing proteins have been identified to date. StAR, a protein targeted to mitochondria, stimulates the movement of cholesterol from the outer to the inner mitochondrial membranes, where it is metabolized into pregnenolone in steroidogenic cells. MLN64, the START domain protein most closely related to StAR, is localized to late endosomes along with other proteins involved in sterol trafficking, including NPC1 and NPC2, where it has been postulated to participate in sterol distribution to intracellular membranes. To investigate the role of MLN64 in sterol metabolism, we created mice with a targeted mutation in the Mln64 START domain, expecting to find a phenotype similar to that in humans and mice lacking NPC1 or NPC2 (progressive neurodegenerative symptoms, free cholesterol accumulation in lysosomes). Unexpectedly, mice homozygous for the Mln64 mutant allele were viable, neurologically intact, and fertile. No significant alterations in plasma lipid levels, liver lipid content and distribution, and expression of genes involved in sterol metabolism were observed, except for an increase in sterol ester storage in mutant mice fed a high fat diet. Embryonic fibroblast cells transfected with the cholesterol side-chain cleavage system and primary cultures of granulosa cells from Mln64 mutant mice showed defects in sterol trafficking as reflected in reduced conversion of endogenous cholesterol to steroid hormones. These observations suggest that the Mln64 START domain is largely dispensable for sterol metabolism in mice.

Filiaciones:
Kishida T.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Kostetskii I.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Zhang Z.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Martinez F.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Liu P.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Walkley S.U.:
 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, United States

Dwyer N.K.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Blanchette-Mackie E.J.:
 Lipid Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, MD 20892, United States

Radice G.L.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

Strauss III J.F.:
 Ctr. for Res. Repro./Women's Health, Univ. of Pennsylvania School of Med., Philadelphia, PA 19104, United States

 Ctr. for Res. Repro./Women's Health, 1354 BRB, 421 Curie Blvd., Philadelphia, PA 19104, United States
ISSN: 00219258
Editorial
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA, Estados Unidos America
Tipo de documento: Article
Volumen: 279 Número: 18
Páginas: 19276-19285
WOS Id: 000221041500141
ID de PubMed: 14963026
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