Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most abundant phospholipids in all mammalian cell membranes. In the 1950s, Eugene Kennedy and co-workers performed groundbreaking research that established the general outline of many of the pathways of phospholipid biosynthesis. In recent years, the importance of phospholipid metabolism in regulating lipid, lipoprotein and whole-body energy metabolism has been demonstrated in numerous dietary studies and knockout animal models. The purpose of this review is to highlight the unappreciated impact of phospholipid metabolism on health and disease. Abnormally high, and abnormally low, cellular PC/PE molar ratios in various tissues can influence energy metabolism and have been linked to disease progression. For example, inhibition of hepatic PC synthesis impairs very low density lipoprotein secretion and changes in hepatic phospholipid composition have been linked to fatty liver disease and impaired liver regeneration after surgery. The relative abundance of PC and PE regulates the size and dynamics of lipid droplets. In mitochondria, changes in the PC/PE molar ratio affect energy production. We highlight data showing that changes in the PC and/or PE content of various tissues are implicated in metabolic disorders such as atherosclerosis, insulin resistance and obesity. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Recent studies have indicated that direct intestinal secretion of plasma cholesterol significantly contributes to fecal neutral sterol loss in mice. The physiological relevance of this novel route, which represents a part of the reverse cholesterol transport pathway, has not been directly established in vivo as yet. We have developed a method to quantify the fractional and absolute contributions of several cholesterol fluxes to total fecal neutral sterol loss in vivo in mice, by assessing the kinetics of orally and intravenously administered stable isotopically labeled cholesterol combined with an isotopic approach to assess the fate of de novo synthesized cholesterol. Our results show that trans-intestinal cholesterol excretion significantly contributes to removal of blood-derived free cholesterol in C57Bl6/J mice (33% of 231 mol/kg/day) and that pharmacological activation of LXR with T0901317 strongly stimulates this pathway (63% of 706 mol/ kg/day). Trans-intestinal cholesterol excretion is impaired in mice lacking Abcg5 (؊4%), suggesting that the cholesterol transporting Abcg5/Abcg8 heterodimer is involved in this pathway. Our data demonstrate that intestinal excretion represents a quantitatively important route for fecal removal of neutral sterols independent of biliary secretion in mice. This pathway is sensitive to pharmacological activation of the LXR system. These data support the concept that the intestine substantially contributes to reverse cholesterol transport. Reverse cholesterol transport (RCT)3 is defined as the flux of excess cholesterol from peripheral tissues toward the liver followed by biliary secretion and subsequent disposal via the feces (1). Accumulation of cholesterol in macrophages in the vessel wall is considered a primary event in the development of atherosclerosis and, therefore, removal of excess cholesterol from these cells is of crucial importance for prevention and/or treatment of atherosclerotic cardiovascular diseases. It is generally accepted that HDL is the obligate transport vehicle in RCT and that plasma HDL levels reflect the capacity to accommodate this flux. In line herewith, HDL-raising therapies are currently considered as a promising strategy for prevention and treatment of atherosclerotic cardiovascular diseases (2). In the "classical" scenario, the liver has a central role in RCT (3). Biliary secretion of free cholesterol, facilitated by the heterodimeric ABC-transporter ABCG5/ABCG8 (4), and hepatic conversion of cholesterol into bile acids followed by fecal excretion are referred to as the main routes for quantitatively important elimination of cholesterol from the body. Fecal excretion of sterols is stimulated upon whole body activation of the liver X receptor (LXR, NR1H2/3), a member of the nuclear receptor family for which oxysterols have been identified as natural ligands (5). LXR regulates expression of several genes involved in RCT and activation of LXR by synthetic agonists leads to elevated plasma HDL-cholesterol levels, increased hepatobiliary cholestero...

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Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPAR ␦ may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPAR ␦ activation by GW610742 were evaluated in wild-type and Abca1-deficient ( Abca1 ؊ / ؊ ) mice that lack HDL. Treatment with GW610742 resulted in an ‫ف‬ 50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1 ؊ / ؊ mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1 ؊ / ؊ mice and unaltered upon treatment. Unexpectedly, PPAR ␦ activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1 , Abcg5 , Abcg8 , and 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein NiemannPick C1-like 1 ( Npc1l1 ) in the intestine. PPAR ␦ activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPAR ␦ is a promising target for drugs aimed to treat or prevent atherosclerosis. -van der Veen, J. N., J. K. Kruit, R. Havinga, J. Plasma levels of HDL-cholesterol are inversely related to the development of atherosclerosis (1). This protective effect has been attributed to a role of HDL in reverse cholesterol transport (RCT), defined as the flux of excess cholesterol from peripheral cells to nascent HDL particles followed by transport to the liver. The liver is able to secrete cholesterol into bile, either as free cholesterol or after conversion into bile salts, for removal via the feces. Stimulation of HDL-mediated cholesterol efflux is considered an attractive approach to diminish the development of atherosclerosis.ABCA1 is considered to be essential in RCT (2). ABCA1 is ubiquitously expressed and probably involved in the formation of pre ␤ -HDL particles and the efflux of cholesterol from peripheral tissues toward HDL (3). HDL is considered a major source for bile-destined cholesterol (4). However, we recently demonstrated that, despite the absence of HDL, hepatobiliary cholesterol flux and fecal sterol excretion are not affected in Abca1-deficient ( Abca1 Ϫ / Ϫ ) mice (5, 6). The ABCG5/ABCG8 heterodimer was recently shown to be of crucial importance for hepatobiliary cholesterol secretion and for transport of cholesterol from enterocytes back into the intestinal lumen, thereby promoting net cholesterol removal from the body (7,8).Several genes involved in the control of cholesterol meAbbreviations: Abca1 Ϫ / Ϫ , Abca1-deficient; FPLC, fast-protein liquid chromatography; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme...

Phosphatidylethanolamine (PE) N-methyltransferase (PEMT) catalyzes the synthesis of phosphatidylcholine (PC) in the liver. Mice lacking PEMT are protected against diet-induced obesity and insulin resistance. We investigated the role of PEMT in hepatic carbohydrate metabolism in chow-fed mice. A pyruvate tolerance test revealed that PEMT deficiency greatly attenuated gluconeogenesis. The reduction in glucose production was specific for pyruvate; glucose production from glycerol was unaffected. Mitochondrial PC levels were lower and PE levels were higher in livers from Pemt 2/2 compared with Pemt +/+ mice, resulting in a 33% reduction of the PC-to-PE ratio. Mitochondria from Pemt 2/2 mice were also smaller and more elongated. Activities of cytochrome c oxidase and succinate reductase were increased in mitochondria of Pemt 2/2 mice. Accordingly, ATP levels in hepatocytes from Pemt 2/2 mice were double that in Pemt +/+ hepatocytes. We observed a strong correlation between mitochondrial PC-to-PE ratio and cellular ATP levels in hepatoma cells that expressed various amounts of PEMT. Moreover, mitochondrial respiration was increased in cells lacking PEMT. In the absence of PEMT, changes in mitochondrial phospholipids caused a shift of pyruvate toward decarboxylation and energy production away from the carboxylation pathway that leads to glucose production.

Background: Most hepatic triacylglycerols are believed to originate from fatty acids released from adipose tissue. Results: Lipoprotein phosphatidylcholine is taken up by the liver and converted into triacylglycerols in vivo. Conclusion: Lipoprotein-associated phosphatidylcholine is a quantitatively significant source of hepatic triacylglycerols. Significance: The role of lipoprotein phosphatidylcholine should now be factored into our thinking about the development of hepatic steatosis.

Plö sch, Torsten, Jelske N. van der Veen, Rick Havinga, Nicolette C. A. Huijkman, Vincent W. Bloks, and Folkert Kuipers. Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice. Am J Physiol Gastrointest Liver Physiol 291: G414 -G423, 2006. First published April 13, 2006; doi:10.1152/ajpgi.00557.2005.-The ATP-binding cassette (ABC) half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates the secretion of plant sterols and cholesterol by hepatocytes into bile and their apical efflux from enterocytes. We addressed the putative rate-controlling role of Abcg5/Abcg8 in hepatobiliary cholesterol excretion in mice during (maximal) stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output rates were reduced by 82% and 35%, respectively, in chow-fed Abcg5 Ϫ/Ϫ mice compared with wild-type mice. When mice were infused with the hydrophilic BS tauroursodeoxycholate, similar relative increases in bile flow, BS output, PL output, and total sterol output were observed in wild-type, Abcg5 ϩ/Ϫ , and Abcg5 Ϫ/Ϫ mice. Maximal cholesterol and PL output rates in Abcg5 Ϫ/Ϫ mice were only 15% and 69%, respectively, of wild-type values. An infusion of increasing amounts of the hydrophobic BS taurodeoxycholate increased cholesterol excretion by 3.0-and 2.4-fold in wild-type and Abcg5 Ϫ/Ϫ mice but rapidly induced cholestasis in Abcg5 Ϫ/Ϫ mice. Treatment with the liver X receptor (LXR) agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (fourfold), concomitant with the induction of Abcg5/Abcg8 expression, but not in Abcg5 Ϫ/Ϫ mice. In a separate study, mice were fed chow containing 1% (wt/wt) cholesterol. As expected, hepatic expression of Abcg5 and Abcg8 was strongly induced (fivefold and fourfold) in wild-type but not LXR-␣-deficient (Lxra Ϫ/Ϫ ) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type mice and 2.0-fold in Lxra Ϫ/Ϫ mice, upon cholesterol feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, our data demonstrate that Abcg5/Abcg8 heterodimer-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.ATP-binding cassette transporter; bile formation; biliary lipids; canalicular transport MUTATIONS in the ATP binding-cassette (ABC) half-transporters ABCG5 and ABCG8 cause sitosterolemia (3, 23), which is characterized by the accumulation of plant sterols in the body (4). Data indicate that ABCG5 and ABCG8, which are highly expressed in the liver and small intestine, heterodimerize into a functional complex (3,12). Mutations in either one of the genes cause the biochemical hallmarks of the disease in humans (3, 23) as well as in mouse models (18,27). The daily intake of plant sterols, i.e., sitosterol and campesterol, from a "Western-type" diet is in the same o...

Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1, Abcg5, and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1, Abca1, Abcg5, and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% (P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRalpha-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRalpha independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat.