Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.

Lipid transfer inhibitor protein (LTIP) is a regulator of cholesteryl ester transfer protein (CETP) function. Factors affecting plasma LTIP levels are poorly understood. In humans, plasma LTIP is elevated in hypercholesterolemia. To define possible mechanisms by which hyperlipidemia modifies LTIP, we investigated the effects of hypercholesterolemic diets on plasma LTIP and mRNA levels in experimental animals. The hamster, which naturally expresses CETP, was shown to express LTIP. Hamster LTIP mRNA, exclusively detected in the liver, defined a predicted LTIP protein that is 69% homologous to human, with an isoelectric point of 4.15 and Mr 5 ?16.4 kDa. Hyperlipidemia induced by feeding hydrogenated coconut oil, cholesterol, or both lipids increased plasma LTIP mass up to 2.5-fold, with LTIP mass correlating strongly with plasma cholesterol levels. CETP mass was similarly affected by these diets. In contrast, these diets reduced LTIP hepatic mRNA levels by .50%, whereas CETP mRNA was increased. Similar results for both CETP and LTIP were also observed in cholesterolfed rabbits. In conclusion, we report in hamster and rabbit that dietary lipids regulate LTIP. Diet-induced hypercholesterolemia markedly increased plasma LTIP mass while concomitantly depressing LTIP gene expression. CETP and LTIP have distinct responses to dietary lipids.-Izem, L., and R. E. Morton. Molecular cloning of hamster lipid transfer inhibitor protein (apolipoprotein F) and regulation of its expression by hyperlipidemia. J. Lipid Res. 2009. 50: 676-684. Supplementary key words rabbit • cholesterol • hydrogenated coconut oil Cholesteryl ester transfer protein (CETP) is an important regulator of lipoprotein composition, and its activity affects plasma lipoprotein levels (1-3). Lipid transfer inhibitor protein (LTIP), also known as apolipoprotein F (apoF), impacts CETP activity in a unique way compared with other factors that have been proposed to regulate CETP activity. Unlike general inhibitors of CETP activity, LTIP tailors CETP-mediated transfer events, inhibiting some and promoting others (4, 5). We have proposed that the balance of CETP and LTIP activities is important in defining the flux of CETP substrates, cholesteryl ester, and triglyceride, between lipoproteins (5-7).Factors affecting plasma levels of LTIP are poorly understood. In several human studies, LTIP levels were shown to correlate negatively with triglyceride levels (6, 8), although this correlation appears to occur only in males (6). However, LTIP levels are elevated in hypercholesterolemia (8). In comparison, CETP levels are increased in hypercholesterolemic subjects and typically unchanged in hypertriglyceridemic subjects (9-11). In cholesterol-fed animals, increased plasma CETP levels are accompanied by marked increases in hepatic and extrahepatic CETP mRNA (12-15), but it is not known how cholesterol feeding affects plasma levels of LTIP or LTIP gene expression.To understand the changes in plasma LTIP that are observed in various hyperlipidemic patient populat...

Section: Discussionmentioning

confidence: 90%

Molecular cloning of hamster lipid transfer inhibitor protein (apolipoprotein F) and regulation of its expression by hyperlipidemia

Izem

Morton

2009

“…6). One possible explanation for this is suggested by Woolett et al (13,14), who have shown that feeding SFA to hamsters led to a down-regulation of the LDLR. This would be expected to result in an increase in the net secretion of apoB-containing lipoproteins (because of decreased re-uptake of newly secreted apoB-lipoproteins, as shown in vitro (40) and in vivo (41).…”

Section: Downloaded Frommentioning

confidence: 97%

“…General conclusions have been that diets rich in polyunsaturated fat tend to lower plasma cholesterol and apoB-100 levels, and that diets rich in saturated fats tend to elevate these parameters. Most of the mechanistic studies of these effects have been performed in intact animals and have focused on the ability of the types of dietary fat to affect LDL receptor (LDLR) activity and, thereby, plasma lipoprotein clearance (13,14). In contrast, comparatively few studies have directly examined another way in which the type of dietary fat can influence plasma lipoprotein and lipid levels-namely, by the regulation of hepatic lipoprotein production.…”

mentioning

confidence: 99%

Myristic acid increases dense lipoprotein secretion by inhibiting apoB degradation and triglyceride recruitment

Kummrow

Hussain

Pan

et al. 2002

Fatty acids of varying lengths and saturation differentially affect plasma apolipoprotein B-100 (apoB-100) levels. To identify mechanisms at the level of production, rat hepatoma cells, McA-RH7777, were incubated with [ 35 S]methionine and either fatty acid-BSA complexes or BSA alone. There were increases in labeled apoB-100 secretion with saturated fatty acids palmitic and myristic (MA) (153 ؎ 20% and 165 ؎ 11%, respectively, relative to BSA). Incubation with polyunsaturated docosahexaenoic acid (DHA) decreased secretion to 26 ؎ 2.0%, while monounsaturated oleic acid (OA) did not change it. In pulse-chase studies, MA treatment resulted in reduced apoB-100 degradation, in agreement with its promotion of secretion. In triglyceride (TG) studies, synthesis was stimulated equally by OA, MA, and DHA, but TG secretion was relatively decreased with MA and DHA. With OA, the majority of newly secreted apoB100-lipoproteins was d р 1.006, but with MA, they were much denser (1.063 Ͻ d). Furthermore, the relative recruitment of newly synthesized TG to lipoproteins was impaired with MA. We conclude that mechanisms for effects of specific dietary fatty acids on plasma lipoprotein levels may include changes in hepatic production. In turn, hepatic production may be regulated by specific fatty acids at the steps of apoB-100 degradation and the recruitment of nascent TG to lipoprotein particles. -Kummrow, E., M. M. Hussain, M. Pan, J. B. Marsh, and E. A. Fisher. Myristic acid increases dense lipoprotein secretion by inhibiting apoB degradation and triglyceride recruitment.

“…Total cholesterol concentrations were determined enzymatically (Thermo Scientific, Waltham, MA). Plasma LDL-and HDL-cholesterol concentrations were determined by simultaneously separating plasma at densities of 1.020 and 1.063 g/ml and measuring the content of cholesterol in the top and bottom of each tube by gas-liquid chromatography using stigmastanol as an internal standard (42). Tissues were saponified and cholesterol content measured by gas-liquid chromatography.…”

Section: Plasma Lipoprotein and Tissue Cholesterol Concentrationsmentioning

confidence: 99%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

The fetus has a high requirement for cholesterol and synthesizes cholesterol at elevated rates. Recent studies suggest that fetal cholesterol also can be obtained from exogenous sources. The purpose of the current study was to examine the transport of maternal cholesterol to the fetus and determine the mechanism responsible for any cholesterol-driven changes in transport. Studies were completed in pregnant hamsters with normal and elevated plasma cholesterol concentrations. Cholesterol feeding resulted in a 3.1-fold increase in the amount of LDL-cholesterol taken up by the fetus and a 2.4-fold increase in the amount of HDL-cholesterol taken up. LDL-cholesterol was transported to the fetus primarily by the placenta, and HDL-cholesterol was transported by the yolk sac and placenta. Several proteins associated with sterol transport and efflux, including those induced by activated liver X receptor, were expressed in hamster and human placentas: NPC1, NPC1L1, ABCA2, SCP-x, and ABCG1, but not ABCG8. NPC1L1 was the only protein increased in hypercholesterolemic placentas. Thus, increasing maternal lipoprotein-cholesterol concentrations can enhance transport of maternal cholesterol to the fetus, leading to 1) increased movement of cholesterol down a concentration gradient in the placenta, 2) increased lipoprotein secretion from the yolk sac (shown previously), and possi- Cholesterol is essential for normal fetal development. Possibly the most noted role of cholesterol is as a structural component of membranes. Sterols are also the precursor for bile acids, steroid hormones, and oxysterols, which are all synthesized by the fetus and regulate various cellular processes. Cholesterol is also required for activation of sonic hedgehog (Shh), a protein involved in brain development, and for propagation of the Shh signal (1, 2). Cholesterol is obtained endogenously by de novo synthesis and exogenously by transfer of maternal cholesterol to the fetus. Interestingly, maternal plasma triglyceride and cholesterol concentrations increase during pregnancy in humans (3, 4), possibly an adaptation to maternal and fetal needs. However, whether these changes in maternal lipoprotein concentrations result in increased transport of maternal cholesterol to the fetus is unclear.Since the fetus does not come in direct contact with the maternal circulation, maternal cholesterol destined for the fetus must initially be taken up by the placenta and yolk sac prior to transport and delivery to the fetus. Indeed, the placenta and yolk sac take up maternal LDL-and HDLcholesterol at relatively elevated rates compared with other peripheral tissues (5). LDL is taken up by the LDL receptor (LDLR), which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (5, 6). LDL-derived sterol is transported to the lysosome/endosome pathway where the ester bond is hydrolyzed (7). The unesterified cholesterol is then transported by NiemannThese studies were supported by grants HD34089 (LAW) and GM31651 (FS) from the...