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Cholesterol and Its Biosynthesis in Normal and Malignant Lymphocytes¹

The Jackson Laboratory,² Bar Harbor, Maine, 04609

The presently available information on the role and function of cholesterol in plasma membranes of mammalian cells has been reviewed extensively before. This paper restricts itself to briefly summarize some observations gathered in our laboratory and in those of other investigators which directly address themselves to the regulation of the biosynthesis of cholesterol and its possible significance in immunocompetent cells. It is suggested that de novo synthesis of cholesterol represents a critical metabolic step for proliferation and, possibly also, differentiation of lymphoid cells such as cytotoxic T-cells. De novo synthesis of cholesterol is regulated specifically by a feedback mechanism involving oxygenated derivatives of cholesterol. Some of these oxidation products are known to be generated spontaneously from cholesterol, which in itself is not affecting the activity of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34). At present, it is not known to what extent oxidized derivatives of cholesterol contaminate the human diet. If they do, their effects on the immune system may be significant, and further investigations on such minor yet very potent and naturally occurring compounds in the diet are needed to understand the etiology of several human diseases. These compounds may also be of therapeutic value in the treatment of some malignant disorders.

¹ Presented at the Workshop on Fat and Cancer, December 10 to 12, 1979, Bethesda, Md. This research is supported by Grant CA 19305 from the NIH.

² The Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.