Currently, the prevention and treatment of CVD have been a global focus since CVD is the number one cause of mortality and morbidity. In the pathogenesis of CVD, it was generally thought that impaired cholesterol homeostasis might be a risk factor. Cholesterol homeostasis is affected by exogenous factors (i.e. diet) and endogenous factors (i.e. certain receptors, enzymes and transcription factors). In this context, the number of studies investigating the potential mechanisms of dietary fatty acids on cholesterol homeostasis have increased in recent years. As well, the cluster of differentiation 36 (CD36) receptor is a multifunctional membrane receptor involved in fatty acid uptake, lipid metabolism, atherothrombosis and inflammation. CD36 is proposed to be a crucial molecule for cholesterol homeostasis in various mechanisms including absorption/reabsorption, synthesis, and transport of cholesterol and bile acids. Moreover, it has been reported that the amount of fatty acids and fatty acid pattern of the diet influence the CD36 level and CD36-mediated cholesterol metabolism principally in the liver, intestine and macrophages. In these processes, CD36-mediated cholesterol and lipoprotein homeostasis might be impaired by dietary SFA and trans-fatty acids, whereas ameliorated by MUFA in the diet. The effects of PUFA on CD36-mediated cholesterol homeostasis are controversial depending on the amount of n-3 PUFA and n-6 PUFA, and the n-3:n-6 PUFA ratio. Thus, since the CD36 receptor is suggested to be a novel nutrient-sensitive biomarker, the role of CD36 and dietary fatty acids in cholesterol metabolism might be considered in medical nutrition therapy in the near future. Therefore, the novel nutritional target of CD36 and interventions that focus on dietary fatty acids and potential mechanisms underlying cholesterol homeostasis are discussed in this review.

The last few decades have witnessed a global rise in the number of older individuals. Despite this demographic shift, morbidity within this population group is high. Many factors influence healthspan; however, an obesity pandemic is emerging as a significant determinant of older people’s health. It is well established that obesity adversely affects several metabolic systems. However, due to its close association with overall cardiometabolic health, the impact that obesity has on cholesterol metabolism needs to be recognised. The aim of the present review is to critically discuss the effects that obesity has on cholesterol metabolism and to reveal its significance for healthy ageing.

Whole-grain highland hull-less barley (WHLB) contains high amounts of bioactive compounds that potentially exhibit cholesterol-lowering effects. This study investigated the hypocholesterolaemic effect of WHLB. A total of seventy-two male Sprague–Dawley rats were divided into four groups and were fed with the normal control diet, high-fat diet (HFD) and HFD containing low or high dose (10 or 48·95 %) of WHLB. High dose of WHLB significantly decreased the organ indexes of liver and abdominal fat and lipid levels of plasma and liver in HFD rats. The lipid regulation effect of WHLB, which was reconfirmed through hepatocyte morphologic observation, was accompanied by a large excretion of bile acids in the small intestinal contents and the faeces. Real-time PCR analyses, which were further reconfirmed through Western blot analyses, revealed that a high dose of WHLB significantly enhanced the hepatic expressions of AMP-activated protein kinase α, cholesterol 7α-hydroxylase, LDL receptor, liver X receptor, and PPARα and decreased the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It also enhanced the ileal expression of farnesoid X receptor and resulted in the decrease of expression of apical sodium-dependent bile acid transporter. WHLB exhibited hypocholesterolaemic effects mainly by inhibiting cholesterol synthesis, cholesterol accumulation in peripheral tissue, and bile acid reabsorption and by stimulating bile acid synthesis.

n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats.

To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.

Plant sterol (PS)-supplemented foods are recommended to help in lowering serum LDL-cholesterol (LDL-C). Few studies have examined the efficacy of PS-enriched skimmed milk (SM) or semi-SM enriched with vegetable fat (PS-VFM). There is also insufficient information on factors predictive of LDL-C responses to PS. We examined the effects of PS-SM (0·1 % dairy fat) and PS-VFM (0·1 % dairy fat plus 1·5 % vegetable fat) on serum lipids and non-cholesterol sterols in hypercholesterolaemic individuals. In a placebo-controlled, crossover study, forty-three subjects with LDL-C>1300 mg/l were randomly assigned to three 4-week treatment periods: control SM, PS-SM and PS-VFM, with 500 ml milk with or without 3·4 g PS esters (2 g free PS). Serum concentrations of lipids and non-cholesterol sterols were measured. Compared to control, LDL-C decreased by 8·0 and 7·4 % (P < 0·015, both) in the PS-SM and PS-VFM periods, respectively. Serum lathosterol:cholesterol (C) ratios increased by 11–25 %, while sitosterol:C and campesterol:C ratios increased by 70–120 % with both the PS-fortified milk. Adjusted LDL-C reductions were variably enhanced in participants with basal low serum lathosterol/C or conversely high sitosterol/C and campesterol/C. Subjects with post-treatment serum PS:C ratios above the median showed mean LDL-C changes of − 5·9 to − 10·4 %, compared with 1·7 to − 2·9 % below the median. In conclusion, consumption of 2 g/d of PS as PS-SM and PS-VFM lowered LDL-C in hypercholesterolaemic subjects to a similar extent. Basal and post-treatment changes in markers of cholesterol metabolism indicating low cholesterol synthesis and high cholesterol absorption predicted improved LDL-C responses to PS.

Methionine has been shown to increase plasma cholesterol in animals. In the present study, mechanisms were investigated by which methionine could alter cholesterol metabolism. In the first experiment, forty growing rats were fed four casein-based diets differing in methionine content (2·6, 3·5, 4·5 or 6·0 g/kg) for 14 d. In the second experiment, isolated rat hepatocytes were incubated in media supplemented with 50, 100 or 200 μmol/l methionine. Dietary methionine tended to increase plasma homocysteine concentrations in the rats (P=0·058). A weak positive correlation between circulating homocysteine and plasma cholesterol was observed (R2 0·27, P<0·01). Rats fed 3·5 g/kg or more of methionine had higher concentrations of cholesterol in their plasma, in lipoprotein fractions of density (ρ kg/l) 1·006 < ρ<, 1·063 and ρ>. 1·063, and in liver than rats fed 2·6 g/kg methionine. Rats fed 6 g/kg methionine had a higher hepatic expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol-7α-hydroxylase than rats fed less methionine. The phosphatidylcholine:phosphatidylethanolamine ratio in rat liver increased with rising dietary methionine concentration; the relative mRNA concentrations of phosphatidylethanolamine N-methyltransferase and cystathionine β-synthase remained unaffected. Hepatocytes incubated in media supplemented with 100 or 200 μmol/l methionine had a higher cholesterol synthesis than hepatocytes incubated in a medium supplemented with 50μmol/l methionine; the LDL uptake in hepatocytes was independent of the methionine concentration of the medium. In conclusion, the present study suggests that dietary methionine induces hypercholesterolaemia at least in part via an enhanced hepatic cholesterol synthesis.

The importance of legume proteins in cholesterol metabolism has been recognised, but the hindgut contribution is still unclear. The present work was undertaken to address the role of the caecum–colon in cholesterol metabolism in intact (I) and ileo-rectal anastomosed (IRA) pigs fed with casein or extruded soyabean (ES) diets. Four groups of six growing pigs were assigned to the treatments (casein–I, casein–IRA, ES–I, ES–IRA) for 3 weeks. Plasma total cholesterol, LDL- and HDL-cholesterol were not modified by surgery or diet. In the liver, the ES diet significantly depressed non-esterified, esterified and total cholesterol. The treatments did not affect hepatic 3-hydroxy-3-methylglutaryl CoA reductase, cholesterol 7α-hydroxylase or sterol 27-hydroxylase activities. In the gallbladder bile of ES-fed pigs, total cholesterol was depressed while total bile acid concentration was increased. IRA and the ES diet markedly decreased the biliary bile acid microbial metabolites (namely hyodeoxycholic acid) and increased the primary bile acids (mainly hyocholic acid). The concentration of bile hydrophobic acids was decreased only by the ES diet. Faecal neutral sterol output was increased in ES-fed pigs, but the bile acid and the sum of neutral and acidic steroid outputs were not. Microbial transformation of neutral and acidic steroids was markedly reduced by IRA, especially in the ES-fed pigs. Thus, surgery and ES modulated the steroid profile but the caecum–colon did not seem to play a crucial role in determining cholesterolaemia in pigs.

The present study investigated the digestion and cholesterol-lowering effects of the water-soluble NSP guar gum (GG) and sodium alginate (SA) in laboratory animals. Groups of five male Wistar strain rats were fed semi-purified cholesterol-free diets containing 0, 50 or 100 g NSP source/kg for 21 d which comprised a 14-d adaptation period followed by a 7-d balance period. Weight gain over the balance period and food conversion ratio decreased linearly with increasing NSP intake (P=0.006 and P=0.07 respectively). DM digestibility decreased with increasing NSP intake (P=0.001) and this effect was greater for SA-containing diets compared with GG-containing diets (P=0.001). At the lower inclusion rate, 0.9–1.0 of the additional NSP was digested, but this value fell to 0.8 for both NSP sources at the 100 g/kg inclusion rate, implying that the capacity for near complete digestion of the test NSP had been exceeded. Intestinal tissue mass was increased in response to inclusion of both NSP sources. Caecal digesta pH decreased linearly with additional GG, but increased slightly with consumption of SA. Total caecal short-chain fatty acid concentrations (μmol/g caecal contents) increased markedly with 50 g GG/kg but did not increase further with 100 g GG/kg, and were slightly lower than control values in rats consuming SA. Plasma cholesterol concentration fell linearly (P=0.03) with increasing NSP in the diet and the effect was similar for both GG and SA. Total output of faecal bile acids rose in rats fed 50 g GG/kg and 50 g SA/kg (59 μmol/7 d v. 24 μmol/7 d for control rats) with no further increase at the higher inclusion rate. These results show that SA has a strong hypocholesterolaemic effect in rats which is similar to that of GG, and that this effect is most likely to be mediated through an interruption in the entero-hepatic circulation of bile acids and not through increased hepatic supply of propionate from fermentation of the NSP in the large bowel.

The consumption of fat-enriched diets may alter the uptake and metabolism of chylomicron remnant cholesterol by the liver. To test this hypothesis, [3H]cholesterol-labelled chylomicron remnants derived from different dietary fats were studied in perfused livers both from rats fed on diets enriched in the corresponding fats and from rats fed on a low-fat diet. Livers from rats fed on each of the fat-enriched diets removed similar amounts (34–40 %) of the [3H]cholesterol-labelled remnants added, whereas livers from rats fed on the low-fat diet removed significantly more labelled fish-oil and butter-fat remnants than olive-, maize- or palm-oil remnants. Significantly more remnant [3H]cholesterol was secreted into the perfusate HDL by livers from rats fed on the olive-oil, fish-oil and butter-fat diets when compared with those from rats fed on the low-fat diet or the maize-oil diet. Furthermore, the excretion of remnant [3H]cholesterol via the bile acid was increased by the olive-, maize-, palm- or fish-oil diets, and decreased by the butter-fat diet when compared with the low-fat diet, although the [3H]bile acid excreted remained less on saturated fat diets. This investigation shows that the hepatic uptake and subsequent metabolism of cholesterol from chylomicron remnants is influenced by the type of fat in the diet as well as the fatty acid composition of the particles themselves, and may help to explain some of the hyper- and hypocholesterolaemic effects of saturated and unsaturated fatty acids.

Male Wistar rats were fed on a conventional diet containing normal corn starch or 6 % enzyme-resistant starch originating from either raw or retrograded high-amylose corn starch. Furthermore, the diets were either cholesterol-free or contained 1 % cholesterol and 0·1 % cholic acid. The main objective of this study was to investigate whether the addition of enzyme-resistant starch to a rat conventional diet had any effect on cholesterol metabolism. Therefore, plasma and liver cholesterol concentrations, plasma HDL:LDL cholesterol ratios and neutral steroid and bile acid excretion were determined. No significant effect of enzyme-resistant starch feeding on plasma and liver cholesterol concentrations was found. However, consumption of raw or retrograded high-amylose corn starch resulted in a decrease in esterified and total liver cholesterol concentrations of 24 and 22 %, respectively. This was accompanied by a reduction in plasma esterified and total cholesterol levels of 4 % and a tendency to higher daily faecal coprostanol and total bile acid excretion.

The effect of a mixture of organisms (a probiotic mixture) comprising Bacillus, Lactobacillus, Streptococcus, Clostridium, Saccharomyces and Candida(107–8 colony-forming units/g rice bran of each component) on lipid metabolism was compared with that of L. acidophilus and that of S. faecalis. There were four treatment groups: rice bran (control), the mixture of organisms, L. acihphifus or S. faecds (30g/kg) were given to rats in a fat- and cholesterol-enriched diet for 4 weeks. The serum total cholesterol concentration of the group fed on the mixture of organisms was reduced by 15–33% compared with the other groups at the end of the 4week feeding period (P < 0·05). This group also had a lower hepatic cholesterol concentration (36–44%) than the two single-bacteria groups (P < 0·05). 3-Hydmxy-3-methylglutaryl-Co A reductase (NADPH; EC 1.1.1.34) activities of the mixed-organism and L. acidophifus groups were significantly lower (61–63%) than those of the other groups (P < 0·05); the activity of the S. faecalis group was also signikantly lower (42%) than that of the control group (P < 0·05). The faecal cholesterol and bile acid concentrations of the mixed-organism group increased compared with those of the L. acidophilus and S. faecalis groups (P < 0·05). The capacity of the mixed- organism cells to bind bile salt in vitro was significantly higher (approximately 50%) than that of the singlebacteria cells (P < 0·05). On the other hand, cholesterol micelle formation for the mixed-organism cells was significantly (approximately 9%) lower than that of the singlebacteria cells (P < 0·05). These results indicate that the mixture of organisms decreased the synthesis of cholesterol in the liver and increased the loss of steroids from the intestine, in rats. Thus, the mixture of organisms had a hypocholeaterolaemic role

The effect in rabbits of giving isonitrogenous purified diets containing casein, ovalbumin, fish protein, milk-whey protein and soya-bean protein were compared. The diets were balanced for cholesterol and for the amount and type of fat. When incorporated into low-cholesterol diets (0.8 g cholesterol/kg), casein, ovalbumin and soya-bean protein produced similar levels of serum cholesterol. With a high background of dietary cholesterol (1.5 g/kg), serum cholesterol concentrations increased with soya-bean protein, whey protein, casein and fish protein, in that order. Thus, the hypercholesterolaemic effect of casein in carefully balanced diets was only seen against a high-cholesterol background. The development of hypercholesterolaemia produced by giving fish protein was different from that produced by casein. First, less cholesterol accumulated in the very-low-density-lipoprotein fractions and more in the lipoproteins of higher density with fish protein than with casein. Second, fish protein, unlike casein, did not increase liver cholesterol. Third, transfer of rabbits from a diet containing soya-bean protein to one containing casein resulted in an immediate marked depression in neutral steroid and bile acid excretion in faeces. However, when rabbits were fed on the diet with fish protein after the diet with soya-bean protein, there was no significant depression in neutral steroid output and the depression in bile acid output was delayed. The present study suggests that different animal proteins cause hypercholesterolaemia by different mechanisms.