Apparent coordination of the biosynthesis of lipids in cultured cells: its relationship to the regulation of the membrane sterol:phospholipid ratio and cell cycling.

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Abstract
The coordination of the syntheses of the several cellular lipid classes with one another and with cell cycle control were investigated in proliferating [neonatal rat skeletal muscle] L6 myoblasts and fibroblasts [human embryonic long WI-38 fibroblasts and chick embryo fibroblasts CEF]. Cells cultured in lipid-depleted medium containing 1 of 2 inhibitors of hydroxymethylglutaryl-CoA reductase, 25-hydroxycholesterol or compactin, display a rapid, dose-dependent inhibition of cholesterol synthesis. Inhibition of the syntheses of each of the other lipid classes is 1st apparent after the rate of sterol synthesis is depressed several-fold. After the addition of the inhibitor for 24 h, the syntheses of DNA, RNA and protein also decline. The inhibition of sterol synthesis leads to a 3-fold reduction in the sterol:phospholipid ratio that parallels the development of proliferative and G1 cell cycle arrests and alterations in cellular morphology. All of these responses are reversed upon reinitiation of cholesterol synthesis or addition of exogenous cholesterol. A comparison of the timing of these responses with respect to the development of the G1 arrest indicates that the primary factor limiting cell cycling is the availability of cholesterol provided either from an exogenous source or by de novo synthesis. The G1 appears to be responsible for the general inhibition of macromolecular synthesis in proliferating cells treated with 25-hydroxycholesterol. The apparent coordinated inhibition of lipid synthesis is not a consequence of the G1 arrest but may give rise to it. Sequential inhibition of lipid syntheses is also observed in cycling cells when the synthesis of choline-containing lipids is blocked by choline deprivation and is observed in association with G1 arrests caused by confluence or differentiation. In the nonproliferating cells the syntheses of lipid and protein do not appear coupled.