Ocular functions of Apos A-I, B, E, and J have been discussed elsewhere,
9 21 24 46 47 and we focus herein on the potential functional implications for RPE and choroidal biology of intraocular biosynthesis of ApoC-I and C-II, which, like all Apos, serve as enzyme modulators and receptor ligands in addition to lipid transporters.
45 48 The human
APOC1 and
APOC2 genes are members of a 48-kb cluster on chromosome 19 that includes ApoE and pseudo-ApoC1′. At ∼4.7 kb,
APOC1 is expressed primarily in liver and, significantly, also in lung, skin, testis, and spleen, where transcription is driven by a promoter different from the one responsible for high-level hepatic transcription. In vitro studies indicate that ApoC-I activates lecithin cholesterol acyl transferase (LCAT), inhibits, among others, lipoprotein (LPL) and hepatic lipases that hydrolyze TG in particle cores, and hinders binding and uptake of VLDL to the LDL and VLDL receptors by displacing ApoE on the ligand particles. Notably, both LCAT and LPL are expressed in RPE and choroid.
22 49 Mice expressing human ApoC-I have elevated plasma cholesterol and TG due to elevated VLDL and LDL fractions, elevated plasma nonesterified fatty acids, scaly skin, and hair loss, and ApoC-I deficient mice have 60% higher plasma triglyceride than wild-type and are sensitive to high-fat diets. Of interest, ApoC-I message is reduced, and ApoC-I protein is increased in the brain in Alzheimer disease.
50 Regarding ApoC-II, the 3.4-kb
APOC2 gene is expressed in liver and intestine only. Its function, revealed by study of human mutations, is clearly one of an LPL activator, although studies in mice suggest that this effect depends on ApoC-I concentration. Recently, ApoC-II has joined Apos A-I, A-II, and E as those readily forming amyloid in the absence of lipid to stabilize their amphipathic α-helical domains,
51 of potential interest because drusen contain dispersed supramolecular amyloid assemblies.
52 53 54 The ocular-specific functions of ApoC-I and C-II remain to be determined, but their presence, especially that of ApoC-II, lends further credence to the overall concept of a large ApoB-lp.