Fatty acids, cholesterol, and sphingolipids: interactive regulators and targets for SREBP processing

摘要

Sterol regulatory element-binding protein (SREBPs) have a major role in regulating transcription of many genes involved in lipid biology and pathobiology.In addition to inhibitory effects of cholesterol on cleavage of the precursor of SREBP (pSREBP) to the active mature nuclear form (mSREBP), polyunsaturated fatty acids (PUFA)-but not saturated fatty acids-have a key role in inhibiting formation of the active mSREBP.The ability of PUFA to decrease SREBP-dependent gene transcription is related in part to effects on modulating intracellular cholesterol partitioning and through effects on sphingolipid metabolism Effects related to sphingolipids are due in part to their higher affinity for free cholesterol, as well as to the ability of PUFA to increase cell sphingomyelinase activity leading to production of ceramide. The inhibitory effects of ceramide on SREBP cleavage are associated with the ability of ceramide to inhibit its own de novo intracellular synthesis, which we hypothesize effects normal SREBP trafficking between the endoplasmic reticulum (ER) and Golgi compartments.Our work indicates that intermediates of sphingomyelin metabolism now join cholesterol and fatty acids as important regulators of SREBP processing, and offer new therapeutic targets for disorders of lipid metabolism including dyslipidemias, steatohepatitis, obesity, and type II diabetes.