Interaction of galectin-7 with HMGCS1 in vitro may facilitate cholesterol deposition in cultured keratinocytes.

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase 1 (HMGCS1) was identified to interact with Gal-7, a pro-apoptotic β-galactoside binding protein, by yeast two-hybrid system. Their interaction was confirmed by in vitro β-galactosidase, BIA core and immunoprecipitation assays. Distinct interactive site of HMGCS1was found to reside at Phe-26. The expression of HMGCS1 in cultured keratinocytes was up-regulated by exogenous Gal-7 and down-regulated in Gal-7 siRNA transfected cells. HMGCS1-overexpressing cells were found to induce Gal-7 expression, which suggests that Gal-7 and HMGCS1 expressions are both stimulated by a positive feedback regulation. The amount of cholesterol, a final biosynthetic product of HMGCS1-involved pathway, was increased in Gal-7 treated cells, and was significantly reduced in Gal-7 siRNA transfected cells. The increase of cholesterol level in Gal-7 treated cells was inhibited by wild type HMGCS1 peptide but not by Phe-26 mutated peptide, suggesting that the interaction of Gal-7/HMGCS1 is related to cellular cholesterol level. Foam cells in granulomatous tissues of the specimens from normolipemic cutaneous xanthoma showed positive reactions with the antibodies for Gal-7 and HMGCS1 as well as lipid markers. These results are likely to indicate that Gal-7 induction in epidermal keratinocytes causes both apoptotic cell death and HMGCS1-mediated cholesterol accumulation which will be phagocytized by macrophages. This mechanism may explain the pathogenesis of normolipemic cutaneous xanthoma.