Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.     

Linoleic acid and coronary heart disease

The extent to which higher intakes of linoleic acid (LA) affect risk for coronary heart disease (CHD) is examined by reviewing a wide variety of study types, mostly in humans. In experimental studies, LA has been shown to lower serum levels of low-density lipoprotein cholesterol (LDL-C), especially when substituted for saturated fatty acids. Such an effect would be expected to reduce risk for CHD. In observational studies in which the dietary intake or serum content of LA were either cross-sectionally or prospectively related risk for CHD, higher LA intakes or serum levels have usually been associated with reduced risk. The pooled results from 5 randomized trials where LA was substituted for saturated fatty acids revealed a significant decrease in risk for CHD events with an LA intake 2-3 times current levels. Thus, current recommendations to consume 5-10% of energy from LA are evidence-based, and should not be reduced.     

Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile

Background

Fibroblast growth factor 21 (FGF-21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and lipid metabolism in animal models. The relationship between plasma levels of FGF-21 and coronary heart disease (CHD) in unknown.

Methodology/Principal Findings

This study aimed to investigate the correlation of serum FGF-21 levels and lipid metabolism in the patients with coronary heart disease. We performed a logistic regression analysis of the relation between serum levels of FGF-21 and CHD patients with and without diabetes and hypertension. This study was conducted in the Departments of Endocrinology and Cardiovascular Diseases at two University Hospitals. Participants consisted of one hundred and thirty-five patients who have been diagnosed to have CHD and sixty-one control subjects. Serum FGF-21 level and levels of fasting blood glucose; triglyceride; apolipoprotein B100; HOMA-IR; insulin; total cholesterol; HDL-cholesterol; LDL-cholesterol; and C-reactive protein were measured. We found that median serum FGF-21 levels were significantly higher in CHD than that of control subjects (P<0.0001). Serum FGF-21 levels in CHD patients with diabetes, hypertension, or both were higher than that of patients without these comorbidities. Serum FGF-21 levels correlated positively with triglycerides, fasting blood glucose, apolipoprotein B100, insulin and HOMA-IR but negatively with HDL-C and apolipoprotein A1 after adjusting for BMI, diabetes and hypertension. Logistic regression analysis demonstrated that FGF-21 showed an independent association with triglyceride and apolipoprotein A1.

Conclusions/Significance

High levels of FGF-21 are associated with adverse lipid profiles in CHD patients. The paradoxical increase of serum FGF-21 in CHD patients may indicate a compensatory response or resistance to FGF-21.     

Polymorphisms of the apolipoprotein and angiotensin converting enzyme genes in young North Karelian patients with coronary heart disease

The genes encoding apolipoproteins (apos) A-I, B, C-III and E as well as that encoding the angiotensin converting enyzme (ACE) have been proposed as candidate genes for coronary heart disease (CHD). We determined the common polymorphisms of the apo genes, previously found to influence serum lipid levels at the population level, and the insertion/deletion polymorphism of the ACE gene, recently reported to reflect the risk of myocardial infarction, in 82 very young (mean, 41 years) North Karelian Finns with symptomatic CHD and 50 controls of similar age. Patients with familial hypercholesterolemia had been excluded from this material. None of the polymorphisms examined, including the apo A-I promoter MspI, apo C-III SstI and apo B XbaI restriction fragment polymorphisms, a common variation of apo E (2, 3 and 4 alleles) and an ACE insertion/deletion (I/D) polymorphism, was significantly associated with the risk of premature CHD. Patients with CHD had a higher mean serum LDL cholesterol/HDL cholesterol ratio than controls (3.15±1.30 vs 2.72±0.98, P < 0.05), but no significant associations between the common apo gene polymorphisms and serum lipid levels were disclosed in either group. It is possible that other genetic loci than those proposed to be associated with accelerated atherosclerosis may be more important as risk factors of symptomatic CHD at the age of 40 years.     

Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9

Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfering RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides.     

Advances in Lipid Testing and Management in Patients with Diabetes Mellitus

ObjectiveTo review the pathophysiologic basis for the classic phenotype associated with diabetic dyslipidemia, discuss recent advances in lipid and lipoprotein testing for risk assessment and lipid therapy monitoring, and summarize a systematic approach to the clinical management of diabetic dyslipidemia.MethodsWe review the pertinent literature, including treatment guidelines and results of major clinical trials, and discuss the effectiveness of various pharmacologic interventions for management of lipid levels in patients with diabetes.ResultsThe incidence and prevalence of type 2 diabetes mellitus continue to escalate globally at alarming rates. Diabetes predisposes to multiple microvascular and macrovascular complications, including cardiovascular disease, the number 1 cause of mortality in the United States. The third report of the National Cholesterol Education Program Adult Treatment Panel in 2001 identified diabetes as a coronary heart disease (CHD) risk equivalent, in light of the evidence that CHD risk in persons with diabetes is similar to that of nondiabetic persons with established CHD. Diabetic dyslipidemia is characterized by a constellation of lipid derangements—hypertriglyceridemia, a low concentration of high-density lipoprotein cholesterol (HDL-C), and a high concentration of small, dense low-density lipoprotein (LDL) particles—that accelerate the progression of atherosclerotic disease and the development of atherothrombotic events.ConclusionStatin trials have demonstrated significant reductions in morbidity and mortality from cardiovascular diseases, including in patients with diabetes. Nevertheless, many patients who achieve their LDL cholesterol (LDL-C) goal still have residual CHD risk. Diabetic dyslipidemia contributes to this residual risk because of the increased concentration of atherogenic apolipoprotein B-containing lipoproteins that can persist despite normalized LDL-C levels and low HDL-C levels. Recent clinical trials emphasize the importance of intensive lipid lowering to achieve recommended goals for LDL-C, non-HDL-C, and apolipoprotein B. (Endocr Pract. 2009;15:641-652)     

Inactivation of Semicarbazide-Sensitive Amine Oxidase Stabilizes the Established Atherosclerotic Lesions via Inducing the Phenotypic Switch of Smooth Muscle Cells

Given that the elevated serum semicarbazide-sensitive amine oxidase (SSAO) activity is associated with the severity of carotid atherosclerosis in clinic, the current study aims to investigate whether SSAO inactivation by semicarbazide is beneficial for established atherosclerotic lesions in LDLr knockout mice on a high-fat/high- cholesterol Western-type diet or after dietary lipid lowering. Despite no impact on plasma total cholesterol levels, the infiltration of circulating monocytes into peripheral tissues, and the size of atherosclerotic lesions, abrogation of SSAO activity resulted in the stabilization of established lesions as evidenced by the increased collagen contents under both conditions. Moreover, SSAO inactivation decreased Ly6C^high monocytosis and lesion macrophage contents in hypercholesterolemic mice, while no effect was observed in mice after normalization of hypercholesterolemia by dietary lipid lowering. Strikingly, abrogation of SSAO activity significantly increased not only the absolute numbers of smooth muscle cells (SMCs), but also the percent of SMCs with a synthetic phenotype in established lesions of mice regardless of plasma cholesterol levels. Overall, our data indicate that SSAO inactivation in vivo stabilizes the established plaques mainly via inducing the switch of SMCs from a contractile to a synthetic phenotype. Targeting SSAO activity thus may represent a potential treatment for patients with atherosclerosis.     

Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices

ObjectiveTo compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations.DesignCross sectional study.Setting17 practices within 17 primary care groups in Trent region, United Kingdom.ParticipantsPatients aged 35 years or over taking lipid lowering drugs and with at least two serum cholesterol concentrations recorded on computer.Results1353 of 2469 (54.8%) patients receiving lipid lowering treatment had a last recorded serum cholesterol concentration of ⩽5 mmol/l. Significantly more patients taking statins achieved the target value for serum cholesterol (5 mmol/l) than those taking fibrates (1307 (57%) v 46 (26%); P<0.0001). Atorvastatin and simvastatin were the most effective drugs in achieving the target. Significant differences were found between lipid lowering drugs for the pretreatment serum cholesterol concentration, the most recent cholesterol concentration, and the associated percentage reduction. Atorvastatin and simvastatin achieved the greatest percentage reduction in serum cholesterol concentrations (30.1%, 95% confidence interval 28.8% to 31.4%, and 28.0%, 26.7% to 29.3%, respectively). Although the mean serum cholesterol concentrations in this unselected population tended to be higher than those in clinical trials, the percentage reduction was consistent with the trials.ConclusionThe ability of individual statins to lower serum cholesterol concentration varied, with atorvastatin and simvastatin being the most effective. The percentage reductions agreed with those of randomised controlled trials indicating likely benefits in unselected patients in primary care. As the initial serum cholesterol concentrations were higher than those in randomised controlled trials, target serum cholesterol values of ⩽5 mmol/l may be unrealistic even for patients taking the most efficacious drugs. Also, the higher initial levels could mean that the absolute reduction in cardiovascular risk in primary care patients is greater than thought.

What is already known on this topic

Statins in patients with coronary heart disease help reduce further cardiovascular events and improve survivalThis seems to be a class effect of statins, although there may be important differences in effectiveness between themLess than half of patients in the community who take lipid lowering drugs achieve target serum cholesterol values

What this study adds

Statins vary in their ability to lower serum cholesterol concentration, with atorvastatin and simvastatin achieving the best resultsThe percentage reductions agreed with those found in randomised controlled trialsSince the initial serum cholesterol concentrations were higher than in trials, absolute risk reductions in primary care patients may be greater than thoughtTarget values of ⩽5 mmol/l may be unrealistic even for patients on the most efficacious drugs, because the initial mean cholesterol values of primary care patients are higher than those of patients in trials     

Serum vitamins E, A and lipid peroxidation levels in Kurichias, an Indian tribal population.

Serum vitamins E, A, lipid peroxides, prevalence of dislipidemia, hypertension, obesity and smoking habits were assessed in a volunteer sample of 310 (175 males + 135 females) Kurichias, a tribal population of Kerala, India, who are enjoying longevity relatively free from age associated chronic problems. The mean serum levels of vitamins E and A were higher and lipid peroxides were lower with comparable ages of Indian and Western studies. The prevalence (age standardized to the world population of Segi 95% CI) was obesity 2.87 (1.22-4.53), central obesity 3.71 (2.27-5.15), hypertension 2.70 (1.92-3.48), hypercholesterolemia 0.71 (0.66-0.76), hypertriglyceridemia 2.60 (1.18-4.02) and low high density lipoprotein cholesterol 1.24 (1.07-1.42). Significant negative correlation was observed between vitamins and lipid peroxides. Serum cholesterol and triglycerides showed significant positive correlation with antioxidant vitamins and lipid peroxides. Blood pressure found positive correlation with lipid peroxides and no correlation with vitamins except systolic blood pressure having negative relation with vitamin A. Age showed negative correlation with vitamins and positive correlation with lipid peroxides, whereas lipid peroxides showed positive correlation with obesity only. In multivariate regression analysis serum cholesterol and old age groups were significant predictors of serum antioxidant vitamins and lipid peroxides. The higher levels of antioxidant vitamins, lower levels of lipid peroxides as well as low prevalence of CHD risk factors in Kurichias when compared to other populations suggest that antioxidants or increased intake of foods rich in antioxidants play a key role in their health and longevity.     

Oligomeric proanthocyanidins mitigate cholesterol and cholic acid diet–induced hepatic dysfunction in male Sprague Dawley rats

Dysregulated synthesis of hepatic cholesterol is a critical determinant of atherosclerosis. The combination of cholesterol and cholic acid (CC) diet supplementation to animal models is associated with hepatic dysfunction‐mediated atherosclerosis. The current study was designed to investigate the hepatic cholesterol–lowering effects of oligomeric proanthocyanidins (OPC) in CC diet fed rats. CC diet–induced group exhibited significant increase in the hepatic lipid profile, activities of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (HMGR), PON‐1, LCAT, LPL, and LPO levels, and messenger RNA expression of HMGR, low‐density lipoprotein receptor (LDLr), and HNF‐4α. Administration of OPC (100 mg/kg/bwt) resulted in the significant reduction of lipid profile and HMGR levels, with concomitant increase in the levels of cholesterol‐regulating enzymes and upregulated expression of LDLr and HNF‐4α, which was similar to atorvastatin. Molecular docking studies also revealed that proanthocyanidins had a strong binding affinity to HMGR, similar to atorvastatin. Our findings suggest that OPC regulate the impaired cholesterol metabolism–associated atherosclerosis through hepatic cholesterol–lowering effect.     

Apolipoprotein E phenotypes in Finnish youths: a cross-sectional and 6-year follow-up study

Apolipoprotein E (apoE) polymorphism is a genetic determinant of plasma lipid levels and of coronary heart disease (CHD) risk. We determined the apoE phenotypes and plasma lipid levels in 1577 youths aged 3 to 18 years in 1980. The subjects were randomly selected from five areas of Finland. ApoE phenotyping was performed directly from plasma by isoelectric focusing and immunoblotting. The apoE allele frequencies in the population sample were epsilon 2 = 0.039, epsilon 3 = 0.767, and epsilon 4 = 0.194. There were no differences in the apoE phenotype distribution between East and West Finland or between sexes. The concentrations of serum total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B increased with apoE phenotype in the order of E2/2, E3/2, E4/2, E3/3, E4/3, and E4/4. This increase was already seen in 3-year-old children; it was observed in both sexes, but was clearer in males than in females. The mean levels of high density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride, Lp[a] lipoprotein, and the activity of lecithin:cholesterol acyltransferase did not differ between the apoE phenotypes. The observed differences in serum cholesterol remained fairly stable during the 6-year follow-up from 1980 to 1986, while the mean serum cholesterol concentration in the whole study population decreased by 6.3%. This study confirms the reported higher frequency of the epsilon 4 allele in Finns as compared to most other populations; this may contribute to the high rates of CHD in Finland as compared to most other populations. The results do not, however, explain the higher rate of CHD in East Finland in comparison to the western part of the country.     

Effect of ScrF I polymorphism in the 2nd intron of the HMGCR gene on lipid-lowering response to simvastatin in Chinese diabetic patients

OBJECTIVE: To investigate whether ScrF I polymorphism in the 2nd intron of the HMG-COA reductase gene (HMGCR) influences serum lipid levels and whether this polymorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor, simvastatin. METHODS: One hundred sixty-eight patients with type 2 diabetes mellitus (T2DM) prospectively received simvastatin as a single-agent therapy (20mg day-1 p.o.) for 12 weeks. Serum lipid levels were determined before and after simvastatin treatment. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Subjects with the AA homozygotes had significantly higher serum very low-density lipoprotein cholesterol (VLDL-C) levels than those with the aa homozygotes. In addition, in 168 patients with T2DM who took 20mg simvastatin, the VLDL-C lowering effect by simvastatin in subjects with the aa homozygotes was significantly lower than in those with the Aa heterozygotes and AA homozygotes. CONCLUSIONS: Simvastatin treatment significantly decreased plasma lipids in all patients (P<0.01). Importantly, we demonstrate that ScrF I polymorphism of the HMGCR gene in patients with T2DM groups is associated with significant elevation of serum VLDL-C levels. Subjects with the AA homozygotes had significantly higher serum high VLDL-C levels than those with the Aa heterozygotes and aa homozygotes (AA: 2.18+/-0.51; Aa: 2.04+/-0.59, aa: 1.86+/-0.43, P<0.05 for comparison among three genotypes and P<0.01 for difference between AA and aa). Furthermore, this polymorphism tends to show an enhanced response to an HMG-CoA reductase inhibitor in terms of the cholesterol-lowering effect. In 168 patients with T2DM who took 20mg simvastatin, the VLDL-C lowering effect by simvastatin in subjects with the AA homozygotes was significantly lower than in those with the Aa heterozygotes and aa homozygotes (the reduction in serum VLDL-C levels; 37.03+/-5.67 versus 28.97+/-4.96, P<0.01; 34.62+/-5.87 versus 28.97+/-4.96, P<0.05). These results suggest that the HMGCR gene may serve as a modifier gene for hypercholesterolemia in Chinese diabetic patients.     

Hypocholesterolemic effect of protein prepared from Phaseolus aconitifolius (Jacq.)

Hypocholesterolemic effect of protein concentrate (PC) prepared from moth bean (Phaseolus aconitifolius Jacq.) seeds relative to that of pigeon pea PC and casein were investigated in rats fed on hypercholesterolemic diet containing two per cent cholesterol. The test diets containing casein and legume PCs at 10% protein level were fed to albino rats (Wistar strain) for 45 days. Compared to casein, the two legume PCs produced significantly lower levels of liver total lipid and cholesterol levels except that pigeon pea PC produced only non-significant decrease of total cholesterols in the heart. In addition, the legume PCs produced significantly lower levels of serum triglycerides and total lipids as well as lower levels of total and low-density lipoprotein cholesterol. Moreover, only moth bean PC produced a significantly higher level of serum high-density lipoprotein cholesterol. Generally, PC of moth bean seemed to be more potent at lowering the elevated hepatic and serum lipids and cholesterol levels, which were attributed to the amino acid profile of this lesser-known legume as these indices well correlated with serum cholesterol levels.     

The effect of fat intake and antihypertensive drug therapy on serum lipid profile: a cross-sectional survey of serum lipids in male and female hypertensives

The present study aimed to investigate the effect of betablocker with diuretics therapy on serum cholesterol and high density lipoprotein (HDL-C) lipids in cross-sectional data (age, sex, weight, and body mass index (BMI), smoking/alcoholic consumption) and supplemented vegetarian low-fat diet with daily low fat energy intake, salt intake, duration of drug therapy, and serum protein as effective measures of lowering blood pressure among hypertensives in both males and females. Hypertensive patients on betablocker and/or thiazide therapy were compared in cross-section study with their age, blood pressure, fat intake, serum lipid profile, BMI, and serum albumin in males and females. Dietary fat intake and serum lipid profile were income related. Betablocker and diuretics therapy in combination with dietary fat intervention was beneficial for prolonged dyslipidemia control. Serum cholesterol level was main contributing factor dependent on BMI, duration of drug, and socio-economic factors. Fat intake contributed in hypertension and serum cholesterol levels. A cross-sectional data analysis showed beneficial effects of “low fat-salt-smoking-alcohol consumption and combined polyunsaturated fatty acid with antihypertensive therapy approach” to keep normal dyslipidemia and hypertension. Low fat intake, low salt, smoking, alcohol consumption, and combination of dietary oil supplements with lipid betablockers and diuretic modulators were associated with low hypertension and controlled dyslipidemia in Asian sedentary population.     

Effects of cold stress on serum lipids, lipoproteins, and the activity of lecithin:cholesterol acyltransferase in rabbits

Effects of prolonged stress on lipid metabolism factors were studied for 9 weeks using four groups of young New Zealand rabbits. Two groups (A,B) were rendered atherosclerotic by administering 1% (w/w) cholesterol. One group (C) was subjected to cold stress together with one of the atherosclerotic groups (B); one group was used as control (N). At the end of treatment serum total cholesterol and total lipids of A and B increased significantly, while in stress group (C) a significant decrease was observed. HDL-C levels were reduced in all experimental groups. Triglycerides did not change in A, while they were reduced in both stress groups (C,B). Serum lecithin:cholesterol acyltransferase (LCAT) activity levels of B and C were decreased. Lipoprotein electrophoresis patterns showed a significant redistribution of percentage values in all experimental groups: %LDL-C increased and %VLDL-C decreased in all groups, %HDL-C declined in A and B and did not change in C. The combination of stress and atherosclerosis in rabbits elicits far greater alterations in lipid and lipoprotein profiles than stress or atherosclerosis alone. A stress and atherosclerotic diet combination may be a hazardous one in relation to CHD and atherosclerosis.     

Low density lipoproteins isolated from the blood of patients with ischemic heart disease induce accumulation of lipids in human aortic intima cells

Very low density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) were isolated from the blood of healthy subjects and CHD patients. LDL from the blood of healthy individuals did not raise the intracellular lipid values within 24 h of cultivation. During intracellular lipid values within 24 h of cultivation. During the same incubation period. LDL obtained from the blood of CHD patients caused a 2- to 5-fold rise in cholesterol esters as well as a 1.5- to 3-fold rise in free cholesterol and triglycerides, while the intracellular phospholipid levels remained unchanged. In one of the three cases, the ability to raise the intracellular level of cholesterol esters was demonstrated by VLDL (500 micrograms/ml) derived from CHD patients blood. HDL did not affect the lipid levels in smooth muscle cells cultured from unaffected intima. The obtained data suggests that circulating LDL and, possibly, VLDL in the blood of CHD patients are capable of inducing the accumulation of fat in vascular wall cells.     

Polymorphism of rs873308 near the transmembrane protein 57 gene is associated with serum lipid levels

SNP (single-nucleotide polymorphism) of rs10903129 near the TMEM (transmembrane protein) 57 locus has been associated with TC (total cholesterol) in a previous GWAS (genome-wide association study), but the association of TMEM57 rs873308 SNP and serum lipid levels has not been previously reported. The current study was undertaken to detect the association of the TMEM57 rs873308 SNP and several environmental factors with serum lipid profiles in the Han Chinese and Mulao populations. The genotypes of the TMEM57 rs873308 SNP in 865 individuals of Han Chinese and 902 participants of Mulao nationality were determined by PCR and RFLP (restriction-fragment-length polymorphism) combined with gel electrophoresis and then confirmed by direct sequencing. The T allele frequency of TMEM57 rs873308 SNP was not different between Han and Mulao (23.18% versus 25.72%, P>0.05), but different between males and females in the two ethnic groups (P<0.05). The T allele carriers had lower serum TC, Apo (apolipoprotein) B, HDL-C (high-density lipoprotein cholesterol) levels, ApoA1/ApoB ratio in Han; and lower TAG (triacylglycerol), LDL-C (low-density lipoprotein cholesterol), ApoA1 levels and the ApoA1/ApoB ratio and higher HDL-C levels in Mulao than the T allele non-carriers. There was also different association of the TMEM57 rs873308 SNP and serum lipid profiles between males and females in the both ethnic groups. Serum lipid parameters in the two ethnic groups were also associated with several environmental factors. The association of the TMEM57 rs873308 SNP and serum lipid levels was different in the Han Chinese and Mulao populations and between males and females in the both ethnic groups. There may be a sex-specific association of the TMEM57 rs873308 SNP and serum lipid levels in our study populations.     

Reversal of clofibrate-induced cholesterol oversaturation of bile with chenodeoxycholic acid.

Giving clofibrate 2 g daily to seven patients significantly increased the biliary cholesterol concentration while the proportion of bile acids fell. Five patients on established clofibrate treatment were given 750 mg of chenodeoxycholic acid (CDCA) daily for one month. Biliary lipid analysis after the CDCA treatment showed a significant fall in the proportion of cholesterol and a rise in that of bile acids. The serum lipid concentrations, which had already been reduced by diet and clofibrate, showed a further significant reduction after the introduction of CDCA. This study suggests that CDCA may be usefully combined with clofibrate to reverse the tendency towards cholesterol saturation of bile and enhance the effect of lowering serum lipid concentrations.     

Overexpression of miR-155 in the Liver of Transgenic Mice Alters the Expression Profiling of Hepatic Genes Associated with Lipid Metabolism

Hepatic expression profiling has revealed miRNA changes in liver diseases, while hepatic miR-155 expression was increased in murine non-alcoholic fatty liver disease, suggesting that miR-155 might regulate the biological process of lipid metabolism. To illustrate the effects of miR-155 gain of function in transgenic mouse liver on lipid metabolism, transgenic mice (i.e., Rm155LG mice) for the conditional overexpression of mouse miR-155 transgene mediated by Cre/lox P system were firstly generated around the world in this study. Rm155LG mice were further crossed to Alb-Cre mice to realize the liver-specific overexpression of miR-155 transgene in Rm155LG/Alb-Cre double transgenic mice which showed the unaltered body weight, liver weight, epididymal fat pad weight and gross morphology and appearance of liver. Furthermore, liver-specific overexpression of miR-155 transgene resulted in significantly reduced levels of serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL), as well as remarkably decreased contents of hepatic lipid, TG, HDL and free fatty acid in Rm155LG/Alb-Cre transgenic mice. More importantly, microarray data revealed a general downward trend in the expression profile of hepatic genes with functions typically associated with fatty acid, cholesterol and triglyceride metabolism, which is likely at least partially responsible for serum cholesterol and triglyceride lowering observed in Rm155LG/Alb-Cre mice. In this study, we demonstrated that hepatic overexpression of miR-155 alleviated nonalcoholic fatty liver induced by a high-fat diet. Additionally, carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) was identified as a direct miR-155 target gene that is potentially responsible for the partial liver phenotypes observed in Rm155LG/Alb-Cre mice. Taken together, these data from miR-155 gain of function study suggest, for what we believe is the first time, the altered lipid metabolism and provide new insights into the metabolic state of the liver in Rm155LG/Alb-Cre mice.