Modulation of microsomal glucose‐6‐phosphate translocase activity by free fatty acids: Implications for lipid domain structure in microsomal membranes

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Abstract
Recent studies from this laboratory have demonstrated differential effects of cis‐unsaturated (type A) free fatty acids (FFA) and trans‐unsaturated or saturated (type B) FFA on protein‐mediated surface phenomena, namely, (1) capping on surface immunoglobulin in lymphocytes, (2) receptor‐mediated aggregation of platelets, and (3) adhesion of BHK cells. These results were explained in terms of the FFA‐perturbing specific lipid domains of the plasma membrane with subsequent modulation of the function of proteins occupying those domains. We wanted to determine if a differential effect of type A and type B FFA could be measured in an isolated membrane system, and chose to study the glucose‐6‐phosphate (Glc‐6‐P) translocase:hexose phosphate phosphohydrolase complex of rat liver endoplasmic reticulum. It was found that in intact microsomes, hydrolysis of Glc‐6‐P was inhibited by linoleic acid and linolenic acid. When the permeability barrier of the microsome was disrupted inhibition of hydrolysis was abolished. These results suggested that the Glc‐6‐P translocase was effected by the type A FFA. Importantly, palmitic acid, stearic acid, and elaidic acid had no significant effect on either translocation or hydrolysis of Glc‐6‐P. In addition, other microsomal enzymes, including the serine ethanolamine base exchange protein, diacylglycerol CDP choline phosphotransferase, diacylglycerol CDP ethanolamine phosphotransferase, NAD(P)H cytochrome C reductase, and NADH ferricyanide reductase were not significantly effected by the FFA used in these experiments. The FFA used, although bound to microsomes, were apparently not incorporated into phospholipids, or cyclooxygenated into prostaglandins during the time course of these experiments. Based on previous results showing that cis‐unsaturated FFA exert their greatest perturbing effects in gel‐like lipid, we postulate that the transport protein occupies such a gel‐like lipid domain in the endoplasmic reticulum bilayer.