FIGURE 9:

Model of regulatory role of cholesterol dynamics in the insulin secretory pathway. During proinsulin synthesis and vesicular transport from the ER, there is parallel nonvesicular transport of cholesterol from the ER to the TGN that is mediated by OSBP acting at interorganellar contacts. Cholesterol transport along this pathway simultaneously aids in maintaining the low cholesterol content of the ER and provides cholesterol that is essential for supporting the normal level of stable insulin granule formation. At the TGN, ABCG1- and ABCA1-driven phospholipid translocation and cholesterol redistribution to the inner membrane leaflet promotes formation of new cholesterol-enriched membranes of nascent insulin granules. Deficiency in either OSBP or ABCG1 augments lysosomal degradation of young insulin granules, whereas deficiency of ABCA1 has a smaller effect at this level. The possible pathways of granule degradation (1 vs. 2) are discussed in the text. Exogenous cholesterol suppresses degradation in ABCG1-deficient cells but not in OSBP-deficient cells. The total granule pool that has escaped lysosomal degradation is nevertheless still affected by deficiency of ABCG1, ABCA1, or OSBP as indicated by their diminished exocytosis upon glucose stimulation.