PC-TP/StARD2: Of membranes and metabolism

Abstract

Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) binds phosphatidylcholines, and catalyzes their intermembrane transfer and exchange in vitro. The structure of PC-TP comprises a hydrophobic pocket and a well-defined head group binding site, and its gene expression is regulated by peroxisome proliferator activated receptor-alpha. Recent studies have revealed key regulatory roles for PC-TP in lipid and glucose metabolism. Notably, Pctp(-/-) mice are sensitized to the action of insulin, and exhibit more efficient brown fat-mediated thermogenesis. PC-TP appears to limit access of fatty acids to mitochondria by stimulating the activity of thioesterase superfamily member 2, a newly characterized long-chain fatty acyl-coenzyme A thioesterase. Because PC-TP discriminates between phosphatidylcholines within lipid bilayers, it might function as a sensor that links metabolic regulation to membrane composition.

Figure 1. Structure of PC-TP in complex with phosphatidylcholines

(a) Structure of human PC-TP (blue) in complex with phosphatidylcholine (carbon, yellow; nitrogen, dark blue; oxygen, red; phosphorous, orange). (b) Solvent accessible volume of the binding pocket containing phosphatidylcholine. The phosphatidylcholine molecule (color coding as in panel a) occupies approximately 89% of the lipid binding pocket. (c) Interactions of PC-TP amino acid residues (carbon, light blue; nitrogen, dark blue; oxygen, red) with the glycerol-3-phosphorylcholine moiety of 1-palmitoyl,2-linoleoyl-sn-glycerol-3-phosphorylcholine (palmitoyl-linoleoyl phosphatidylcholine) (color coding as in panel a). The structure of 1,2-dilinoleoyl-sn-glycerol-3-phosphorylcholine (dilinoleoyl phosphatidylcholine) is superimposed (gray). (Modified with permission from reference [28].)

Figure 2. PC-TP interacts with protein domains that are found in multidomain START proteins

(a) Protein-protein interactions. Double-headed dashed arrows depict PC-TP (green) interactions with Them2 and the homeodomain (HD) transcription factor Pax3. These interactions were identified by yeast two-hybrid screening of cDNA libraries from adult liver (left) and mouse embryo (right), respectively. (b) Multidomain protein. Corresponding multidomain START proteins from mammals (left) and plants (right), which contain START domains together with two thioesterase (Thio) domains and a HD plus a leucine zipper (LZ) domain, respectively. BFIT, brown fat inducible thioesterase; CACH, cytosolic acetyl CoA thioesterase; THEA, thioesterase adipose associated. (Reprinted with permission from reference [47].)

Figure 3. Postulated function of PC-TP in the fasting liver

Hepatic uptake of fatty acids during fasting activates (i) PPARα and increases expression of PC-TP and Them2. (ii) The interaction of PC-TP and Them2 stimulates thioesterase activity and prevents fatty acyl-CoA uptake into mitochondria via carnitine palmitoyl transferase I (CPTI). Within the cytoplasm, these fatty acids may activate HNF4α, which promotes hepatic export of lipids and glucose. (iii) Fatty acids may also be reconverted by long chain acyl-CoA synthetases (ACSL) into fatty acyl-CoA, which downregulate insulin signaling. Solid arrows indicate metabolic pathways. Relative thicknesses of lines are drawn in proportion to flux of substrate. Hashed lines indicate stimulatory (arrowheads) and inhibitory (line-stops) regulation.

Figure 4. Postulated function of PC-TP in brown fat

During cold exposure in brown fat, (i) norepinephrine binds to β₃–adrenergic (β₃-AR) receptors coupled with a G protein. This leads to increased cAMP level and phosphorylation of protein kinase A (PKA). (ii) Activated PKA phosphorylates hormone sensitive lipase (HSL), which hydrolyzes triglycerides (TG) into fatty acids and glycerol. (iii) Fatty acids are converted to fatty acyl-CoA by a long-chain acyl-CoA synthetase (ACSL). (iv) Norepinephrine-induced PKA also leads to activation of PKC through phoshoinositide-3-kinase (PI3K). This could cause (v) phosphorylation of phosphatidylcholine transfer protein (PC-TP), which relocates to mitochondria and interacts with thioesterase superfamily member 2 (Them2). This stimulates thioesterase activity and prevents fatty acyl-CoA uptake into mitochondria. (vi) Within mitochondria, fatty acyl-CoAs are oxidized, yielding NADH that is used for production of heat via uncoupling protein 1 (UCP1), which dissipates the proton gradient established by the electron transport chain (ETC). (vii) Under conditions where ATP production by the ETC exceeds heat production, reactive oxygen species (ROS) produced through the ETC provide feedback inhibition of this signaling pathway. Solid arrows indicate metabolic pathways. Hashed lines indicate stimulatory (arrowheads) and inhibitory (line-stops) regulation.