HYPERLIPIDEMIA AND CUTANEOUS ABNORMALITIES IN TRANSGENIC MICE OVEREXPRESSING HUMAN APOLIPOPROTEIN C1

Transgenic mice were generated with different levels of human apolipop rotein C1 (APOC1) expression in liver and skin, At 2 mo of age, serum levels of cholesterol, triglycerides (TG), and FFA were strongly eleva ted in APOC1 transgenic mice compared with wild-type mice, These eleva ted levels of serum cholesterol and TG were due mainly to an accumulat ion of VLDL particles in the circulation, In addition to hyperlipidemi a, APOC1 transgenic mice developed dry and scaly skin with loss of hai r, dependent on the amount of APOC1 expression in the skin. Since thes e skin abnormalities appeared in two independent founder lines, a muta tion related to the specific insertion site of the human APOC1 gene as the cause for the phenotype can be excluded, Histopathological analys is of high expressor APOC1 transgenic mice revealed a disorder of the skin consisting of epidermal hyperplasia and hyperkeratosis, and atrop hic sebaceous glands lacking sebum, In line with these results, epider mal lipid analysis showed that the relative amounts of the sebum compo nents TG and wax diesters in the epidermis of high expressor APOC1 tra nsgenic mice were reduced by 60 and 45%, respectively, In addition to atrophic sebaceous glands, the meibomian glands were also found to be severely atrophic in APOC1 transgenic mice, High expressor APOC1 trans genic mice also exhibited diminished abdominal adipose tissue stores ( a 60% decrease compared with wild-type mice) and a complete deficiency of subcutaneous fat. These results indicate that, in addition to the previously reported inhibitory role of apoC1 on hepatic remnant uptake , overexpression of apoC1 affects lipid synthesis in the sebaceous gla nd and/or epidermis as well as adipose tissue formation, These APOC1 t ransgenic mice may serve as an interesting in vivo model for the inves tigation of lipid homeostasis in the skin.