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BBA - Molecular and Cell Biology of Lipids (v.1733, #1)

Editorial Board (pp. ii).

Structure and regulation of acetyl-CoA carboxylase genes of metazoa by Michael C. Barber; Nigel T. Price; Maureen T. Travers (pp. 1-28).

Acetyl-CoA carboxylase (ACC) plays a fundamental role in fatty acid metabolism. The reaction product, malonyl-CoA, is both an intermediate in the de novo synthesis of long-chain fatty acids and also a substrate for distinct fatty acyl-CoA elongation enzymes. In metazoans, which have evolved energy storage tissues to fuel locomotion and to survive periods of starvation, energy charge sensing at the level of the individual cell plays a role in fuel selection and metabolic orchestration between tissues. In mammals, and probably other metazoans, ACC forms a component of an energy sensor with malonyl-CoA, acting as a signal to reciprocally control the mitochondrial transport step of long-chain fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I (CPT I). To reflect this pivotal role in cell function, ACC is subject to complex regulation. Higher metazoan evolution is associated with the duplication of an ancestral ACC gene, and with organismal complexity, there is an increasing diversity of transcripts from the ACC paralogues with the potential for the existence of several isozymes. This review focuses on the structure of ACC genes and the putative individual roles of their gene products in fatty acid metabolism, taking an evolutionary viewpoint provided by data in genome databases.

Keywords: Gene structure; Transcription; AMP-activated protein kinase; Lipogenesis; β-oxidation; Malonyl-CoA; Biotin; Insulin resistance; Membrane targeting; Alternative splicing; Pseudogene

Function of prokaryotic and eukaryotic ABC proteins in lipid transport by Antje Pohl; Philippe F. Devaux; Andreas Herrmann (pp. 29-52).

ATP binding cassette (ABC) proteins of both eukaryotic and prokaryotic origins are implicated in the transport of lipids. In humans, members of the ABC protein families A, B, C, D and G are mutated in a number of lipid transport and metabolism disorders, such as Tangier disease, Stargardt syndrome, progressive familial intrahepatic cholestasis, pseudoxanthoma elasticum, adrenoleukodystrophy or sitosterolemia. Studies employing transfection, overexpression, reconstitution, deletion and inhibition indicate the transbilayer transport of endogenous lipids and their analogs by some of these proteins, modulating lipid transbilayer asymmetry. Other proteins appear to be involved in the exposure of specific lipids on the exoplasmic leaflet, allowing their uptake by acceptors and further transport to specific sites.Additionally, lipid transport by ABC proteins is currently being studied in non-human eukaryotes, e.g. in sea urchin, trypanosomatides, arabidopsis and yeast, as well as in prokaryotes such as Escherichia coli and Lactococcus lactis. Here, we review current information about the (putative) role of both pro- and eukaryotic ABC proteins in the various phenomena associated with lipid transport. Besides providing a better understanding of phenomena like lipid metabolism, circulation, multidrug resistance, hormonal processes, fertilization, vision and signalling, studies on pro- and eukaryotic ABC proteins might eventually enable us to put a name on some of the proteins mediating transbilayer lipid transport in various membranes of cells and organelles.It must be emphasized, however, that there are still many uncertainties concerning the functions and mechanisms of ABC proteins interacting with lipids. In particular, further purification and reconstitution experiments with an unambiguous role of ATP hydrolysis are needed to demonstrate a clear involvement of ABC proteins in lipid transbilayer asymmetry.

Keywords: Abbreviations; ABC; ATP binding cassette; APLT; aminophospholipid translocase; Cer; ceramide; FA; fatty acid; GlcCer; glucosylceramide; HDL; high density lipoprotein; LTC; leukotriene C; nbd; [; N; -(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]; NBD; nucleotide binding domain; PAF; platelet activating factor; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PS; phosphatidylserine; PXE; pseudoxanthoma elasticum; SL; spin labeled; SM; sphingomyelin; TM, TMD; transmembrane (domain); VLCFA; very long-chain fatty acids; X-ALD; X-linked adrenoleukodystrophyABC protein superfamily; Flippase; Cholesterol; Lipid asymmetry; Lipid exposure; Molecular mechanism

Regulatory enzymes of phosphatidylcholine biosynthesis: a personal perspective by Claudia Kent (pp. 53-66).

Phosphatidylcholine is a prominent constituent of eukaryotic and some prokaryotic membranes. This Perspective focuses on the two enzymes that regulate its biosynthesis, choline kinase and CTP:phosphocholine cytidylyltransferase. These enzymes are discussed with respect to their molecular properties, isoforms, enzymatic activities, and structures, and the possible molecular mechanisms by which they participate in regulation of phosphatidylcholine levels in the cell.

Keywords: Phosphatidylcholine; CDP–choline; Phosphocholine; Choline kinase; Cytidylyltransferase

Substituting dietary linoleic acid with α-linolenic acid improves insulin sensitivity in sucrose fed rats by Ghafoorunissa; Ahamed Ibrahim; Saravanan Natarajan (pp. 67-75).

This study describes the effect of substituting dietary linoleic acid (18:2 n-6) with α-linolenic acid (18:3 n-3) on sucrose-induced insulin resistance (IR). Wistar NIN male weanling rats were fed casein based diet containing 22 energy percent (en%) fat with ∼6, 9 and 7 en% saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) respectively for 3 months. IR was induced by replacing starch (ST) with sucrose (SU). Blends of groundnut, palmolein, and linseed oil in different proportions furnished the following levels of 18:3 n-3 (g/100 g diet) and 18:2 n-6/18:3 n-3 ratios respectively: ST-220 (0.014, 220), SU-220 (0.014, 220), SU-50 (0.06, 50), SU-10 (0.27, 10) and SU-2 (1.1, 2). The results showed IR in the sucrose fed group (SU-220) as evidenced by increase in fasting plasma insulin and area under the curve (AUC) of insulin in response to oral glucose load. In SU-220, the increase in adipocyte plasma membrane cholesterol/phospholipid ratio was associated with a decrease in fluidity, insulin stimulated glucose transport, antilipolytic effect of insulin and increase in basal and norepinephrine stimulated lipolysis in adipocytes. In SU-50, sucrose induced alterations in adipocyte lipolysis and antilipolysis were normalized. However, in SU-2, partial corrections in plasma insulin, AUC of insulin and adipocyte insulin stimulated glucose transport were observed. Further, plasma triglycerides and cholesterol decreased in SU-2. In diaphragm phospholipids, the observed dose dependent increase in long chain (LC) n-3 PUFA was associated with a decrease in LC-n-6 PUFA but insulin stimulated glucose transport increased only in SU-2. Thus, this study shows that the substitution of one-third of dietary 18:2 n-6 with 18:3 n-3 (SU-2) results in lowered blood lipid levels and increases peripheral insulin sensitivity, possibly due to the resulting high LCn-3 PUFA levels in target tissues of insulin action. These findings suggest a role for 18:3 n-3 in the prevention of insulin resistant states. The current recommendation to increase 18:3 n-3 intake for reducing cardiovascular risk may also be beneficial for preventing IR in humans.

Keywords: Adipose tissue; Dietary sucrose; Diaphragm; Fatty acid composition; Glucose transport; Insulin resistance; Linoleic acid; α-Linolenic acid; n-6/n-3 PUFA ratio

Phosphatidylcholine-rich acceptors, but not native HDL or its apolipoproteins, mobilize cholesterol from cholesterol-rich insoluble components of human atherosclerotic plaques by Byung-Hong Chung; Frank Franklin; Ping Liang; Steve Doran; B.H. Simon Cho; Christine A. Curcio (pp. 76-89).

To examine the potential of high density lipoproteins (HDL) to ameliorate atherosclerotic plaques in vivo, we examined the ability of native HDL, lipid-free HDL apolipoproteins (apo HDL), cholesterol-free discoidal reconstituted HDL (R-HDL) comprised of apo HDL and phosphatidylcholine (PC) and PC liposomes to release cholesterol from cholesterol-rich insoluble components of plaques (ICP) isolated from atherosclerotic human aorta. Isolated ICP had a free cholesterol (FC) to phospholipid (PL) mass ratio (0.8–3.1) and a sphingomyelin (SPM) to PC mass ratio (1.2–4.2) that exceeded those of plasma membranes of cultured cells. Suprisingly, native HDL and its apolipoproteins were not able to release cholesterol from ICP. However, R-HDL and PC liposomes were effectively released cholesterol from ICP. The release of ICP cholesterol by R-HDL was dose-dependent and accompanied by the transfer of >8× more PC in the reverse direction (i.e., from R-HDL to ICP), resulting in a marked enrichment of ICP with PC. Compared to R-HDL, PC liposomes were significantly less effective in releasing cholesterol from ICP but were somewhat more effective in enriching ICP with PC. Native HDL was minimally effective in enriching ICP with PC, but became effective after prior in vitro enrichment of HDL with PC from multilamellar PC liposomes. The enrichment of ICP with PC resulted in the dissolution of cholesterol crystals on ICP and allowed the removal of ICP cholesterol by apo HDL and plasma. Our study revealed that the removal of cholesterol from ICP in vivo will be possible through a change in the level, composition, and physical state of ICP lipids mediated by PC-enriched HDL.

Keywords: Abbreviations; apo; apolipoproteins; CE; cholesterylester; CETP; cholesterylester transfer proteins; DMPC; dimyristoyl phosphatidylcholine; FC; free cholesterol; ICP; insoluble component of plaques; LCAT; lecithin:cholesterol acyltransferase; PC; phosphatidylcholine; PL; phospholipids; RBC; red blood cells; RCT; reverse cholesterol transport; R-HDL; reconstituted HDL; SPM; sphingomyelin; TBS; Tris-buffered saline; TLC; thin-layer chromatographyAtherosclerotic plaque; Cholesterol; Cholesterol crystal; Phospholipid; Sphingomyelin; Phosphatidylcholine; High density lipoprotein; Plaque regression

High cholesterol absorption efficiency and rapid biliary secretion of chylomicron remnant cholesterol enhance cholelithogenesis in gallstone-susceptible mice by David Q.-H. Wang; Lunan Zhang; Helen H. Wang (pp. 90-99).

The study of chylomicron pathway through which it exerts its metabolic effects on biliary cholesterol secretion is crucial for understanding how high dietary cholesterol influences cholelithogenesis. We explored a relationship between cholesterol absorption efficiency and gallstone prevalence in 15 strains of inbred male mice and the metabolic fate of chylomicron and chylomicron remnant cholesterol in gallstone-susceptible C57L and gallstone-resistant AKR mice. Our results show a positive and significant ( P<0.0001, r=0.87) correlation between percent cholesterol absorption and gallstone prevalence rates. Compared with AKR mice, C57L mice displayed significantly greater absorption of cholesterol from the small intestine, more rapid plasma clearance of chylomicrons and chylomicron remnants, higher activities of lipoprotein lipase and hepatic lipase, greater hepatic uptake of chylomicron remnants, and faster secretion of chylomicron remnant cholesterol from plasma into bile. All of these increased susceptibility to cholesterol gallstone formation in C57L mice. We conclude that genetic variations in cholesterol absorption efficiency are associated with cholesterol gallstone formation in inbred mice and cholesterol absorbed from the intestine provides an important source for biliary hypersecretion. Differential metabolism of the chylomicron remnant cholesterol between C57L and AKR mice clearly plays a crucial role in the formation of lithogenic bile and gallstones.

Keywords: Abbreviations; Acat2; acyl-CoA:cholesterol acyltransferase gene 2; FPLC; fast performance liquid chromatography; HDL; high density lipoprotein; HMG-CoA; 3-hydroxy-3-methylglutaryl coenzyme A; LDL; low density lipoprotein; QTL; quantitative trait locus; VLDL; very low density lipoproteinBile; Bile flow; Biliary cholesterol secretion; Intestinal cholesterol absorption; Lymph; Nutrition; Gallstone

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BBA - Molecular and Cell Biology of Lipids (v.1733, #1)