An integrated mathematical model of cellular cholesterol biosynthesis and lipoprotein metabolism

Cholesterol regulation is an important aspect of human health. In this work we bring together and extend two recent mathematical models describing cholesterol biosynthesis and lipoprotein endocytosis to create an integrated model of lipoprotein metabolism in the context of a single hepatocyte. The integrated model includes a description of low density lipoprotein (LDL) receptor and cholesterol synthesis, delipidation of very low density lipoproteins (VLDLs) to LDLs and subsequent lipoprotein endocytosis. Model analysis shows that cholesterol biosynthesis produces the majority of intracellular cholesterol. The availability of free receptors does not greatly effect the concentration of intracellular cholesterol, but has a detrimental effect on extracellular VLDL and LDL levels. We test our model by considering its ability to reproduce the known biology of Familial Hypercholesterolaemia and statin therapy. In each case the model reproduces the known biological behaviour. Quantitative differences in response to statin therapy are discussed in the context of the need to extend the work to a more {\it in vivo} setting via the incorporation of more dietary lipoprotein related processes and the need for further testing and parameterisation of {\it in silico} models of lipoprotein metabolism

The Relation of Documented Coronary Artery Disease to Levels of Total Cholesterol and High-Density Lipoprotein Cholesterol

Recommendations for identifying persons at high risk for coronary heart disease are based primarily on levels of total and low-density lipoprotein cholesterol. We examined whether, given knowledge of these levels, information on the high-density lipoprotein cholesterol level would improve the prediction of arteriographically documented coronary artery disease among 591 men. We found that even at levels of total and low-density lipoprotein cholesterol considered desirable, high-density lipoprotein cholesterol was inversely related to disease severity. For example, among the 112 men with a total cholesterol level <180 mg per dl, the mean occlusion score (representing the overall severity of disease) was 107 among men with a high-density lipoprotein cholesterol level =30 mg per dl vs a mean score of 52 among men with levels =45 mg per dl. Furthermore, men with low levels of both low-density lipoprotein cholesterol (<110 mg per dl) and high-density lipoprotein cholesterol (=30 mg per dl) had as much occlusive disease as did men with high levels of both lipoprotein fractions. Given information on the ratio of high-density lipoprotein cholesterol to total cholesterol, the actual levels of the lipoprotein fractions did not improve disease prediction. Our results emphasize the importance of considering high-density lipoprotein cholesterol when assessing coronary heart disease risk. Keywords: cholesterol levels, HDL lipoproteins, LDL lipoproteins, coronary artery disease, lipids

Influence of different fat emulsions with 10 or 20% MCT/LCT or LCT on lipoproteins in plasma of patients after abdominal surgery

In patients after elective abdominal surgery, different fat emulsions were used to compare their efficacy in total parenteral nutrition and in normalizing plasma lipoprotein levels. In five different groups with 5 patients each, half of the nonprotein calories were given as medium-chain triglycerides/ long-chain triglycerides (1:1) or as long-chain triglycerides alone in 10 or 20% fat emulsions or as glucose alone in a control group for 7 days. After surgery, an initial decrease of all plasma lipoprotein components was followed by a different behavior of glyceride-glycerol, cholesterol, phospholipids, and apolipoproteins. Glyceride-glycerol in very-low-density lipoproteins and high-density lipoproteins is increasing during infusion of fat emulsions and decreasing during overnight interruption of infusions. After the 7-day infusion period, there was no significant difference in very-low-density lipoprotein glyceride-glycerol as compared with the values before different infusions, Low-density lipoprotein cholesterol is reaching and exceeding preoperative concentrations between the 4th and the 7th day, most during infusion of 10% fat emulsion and especially due to an increase of free cholesterol, High-density lipoprotein cholesterol and apolipoprotein A-I reach preoperative levels during infusion of fat emulsions but not with glucose alone, Higher than preoperative values are reached in phospholipids with all fat infusions already on day 4, Abnormal lipoprotein X occurred least with the medium-chain/long-chain triglyceride 20% fat-infusion. This fat emulsion is suggested as having the best normalizing effect on plasma lipoproteins and best tolerance in patients after surgery

Importance of measuring non-HDL cholesterol in type 2 diabetes patients.

OBJECTIVE: To study the correlation between Non-high-density lipoprotein and low-density lipoprotein cholesterol in patients with Type 2diabetes mellitus and the proportion of patients achieving Adult Treatment Panel III recommended goals. METHODS: The cross sectional study was conducted at the Diabetic Clinic, Aga Khan University Hospital, Karachi. Data of Type 2 diabetesmellitus patients who attended the clinic bewteen 2007 and 2011 was reviewed. All Type 2 diabetic patients of either gender with fasting lipid profile irrespective of taking lipid lowering therapy were included.Type-1 DM, gestational diabetes, type 2 diabetes patients with pregnancy and those with incomplete data were excluded. Correlation between the low-density lipoprotein and Non-high-density lipoprotein was assessed by applying Cramer V and phi. Proportion of patients achieving Adult Treatment Panel III recommended goals was checked. Multivariable regression was done to identify common factors associated with elevated Non-high-density lipoprotein cholesterol. RESULTS: A total of 1352 patients fulfilling the eligibility criteria were included in the study. Mean age of the patients was 54.5 +/- 11.3 years; 797 (59%) were males; 1122 (83%) had Body Mass Index above 25; and 1016 (75%) had HbA1c \u3e or = 7%. Mean Non-high-density lipoprotein cholesterol was 129 +/- 42 mg/dl. Mean low-density lipoprotein cholesterol was 100 +/- 37 mg/dl. Both low-density lipoprotein \u3c or = 100 and Non-HDL \u3c or = 130 mg/dl was achieved in 645 (48%) patients. It is important to note that although 728 (53.8%) patients achieved target LDL cholesterol of \u3c or = 100 mg/dl, among them 83 (11.4%) had Non-high-density lipoprotein cholesterol still above the target \u3e 130 mg/dl (p \u3c 0.05). Out of 752 patients with Non-high-density lipoprotein cholesterol \u3c or = 130 mg/dl, 645 (86%) had low-density lipoprotein cholesterol below 100 mg/dl. Cramer V and Phi showed that correlation between Non-high-density lipoprotein and low-density lipoprotein cholesterol was 0.71 (p value \u3c 0.01). After adjusting for other covariates, low-density lipoprotein cholesterol \u3e 100 mg/dl was independently associated with having Non-high-density lipoprotein cholesterol \u3e 130 mg/dl (Adjusted Odds Ratio 38.6; 95% Confidance Interval = 28.1-53.1). Similarly, age \u3c or = 60 years was 60% more likely to have Non-high-density lipoprotein cholesterol \u3e 130 mg/dl (Adjusted Odds Ratio 1.6; 95% Confidance Interval = 1.01 - 2.3). Whereas having obesity Body Mass Index \u3e 25 was 3.6 times more associated to have Non-high-density lipoprotein \u3e 130 mg/dl (Adjusted Odds Ratio 3.6; 95% Confidance Interval = 1.6-7.7). In patients with coronary artery disease, combined goal achievement of low-density lipoprotein \u3c or = 70 mg/dl and Non-high-density lipoprotein cholesterol \u3c or = 100 mg/dl was seen in 59 (35%). Among patients with high-density lipoprotein \u3c or = 70 mg/dl, 8 (10%) had Non-high-density lipoprotein \u3e 100 mg/dl (p \u3c 0.05). CONCLUSION: The study showed a correlation between Non-high-density lipoprotein and low-density lipoprotein cholesterol. As measuringNon-high-density lipoprotein cholesterol in Type 2 DM patients is simple, cost-effective and convenient because it does not require 12-hour fasting which may be a risk for hypoglycaemia in these patients, clinicians may choose Non-high-density lipoprotein as a routine measure in everyday practice

Causal relevance of blood lipid fractions in the development of carotid atherosclerosis: Mendelian randomization analysis.

BACKGROUND: Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis. METHODS AND RESULTS: Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01-0.04) and 0.04 mm (95% confidence interval, 0.02-0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT. CONCLUSIONS: Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study

Effects of Diet Composition and Insulin Resistance Status on Plasma Lipid Levels in a Weight Loss Intervention in Women.

BackgroundOptimal macronutrient distribution of weight loss diets has not been established. The distribution of energy from carbohydrate and fat has been observed to promote differential plasma lipid responses in previous weight loss studies, and insulin resistance status may interact with diet composition and affect weight loss and lipid responses.Methods and resultsOverweight and obese women (n=245) were enrolled in a 1-year behavioral weight loss intervention and randomly assigned to 1 of 3 study groups: a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich, higher fat (35% energy), lower carbohydrate (45% energy) diet. Blood samples and data available from 213 women at baseline and at 6 months were the focus of this analysis. Triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterol were quantified and compared between and within groups. Triglycerides decreased in all study arms at 6 months (P<0.05). The walnut-rich diet increased high-density lipoprotein cholesterol more than either the lower fat or lower carbohydrate diet (P<0.05). The walnut-rich diet also reduced low-density lipoprotein cholesterol in insulin-sensitive women, whereas the lower fat diet reduced both total cholesterol and high-density lipoprotein cholesterol in insulin-sensitive women (P<0.05). Insulin sensitivity and C-reactive protein levels also improved.ConclusionsWeight loss was similar across the diet groups, although insulin-sensitive women lost more weight with a lower fat, higher carbohydrate diet versus a higher fat, lower carbohydrate diet. The walnut-rich, higher fat diet resulted in the most favorable changes in lipid levels.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01424007

Transport of apolipoproteins A-I and A-II by human thoracic duct lymph

The daily transport of human plasma apolipoproteins A-I and A-II, triglyceride, and total cholesterol from the thoracic duct lymph into plasma was measured in 2 subjects before and 3 subjects after renal transplantation. Lymph triglyceride transport was ~83% of the daily ingested fat loads, whereas lymph cholesterol transport was consistently greater than the amount of daily ingested cholesterol. Lymph apolipoprotein transport significantly (P < 0.05) exceeded the predicted apolipoprotein synthesis rate by an average of 659±578 mg/d for apolipoprotein A-I and 109±59 mg/d for apolipoprotein A-II among the 5 subjects. It is estimated that 22-77% (apolipoprotein A-I) and 28-82% (apolipoprotein A-II) of daily total body apolipoprotein synthesis takes place in the intestine. Lymph high density lipoprotein particles are mostly high density lipoprotein(2b) and high density lipoprotein(2a) and have a greater overall relative triglyceride content and a smaller relative cholesteryl ester content when compared with homologous plasma high density lipoproteins. The major quantity of both lymph apolipoprotein A-I (81±8%) and apolipoprotein A-II (90±11%) was found within high density lipoproteins with almost all of the remainder found in chylomicrons and very low density lipoproteins. The combined results are consistent with a major contribution of the intestine to total body synthesis of apolipoprotein A-I and apolipoprotein A-II. An important role of lymph in returning filtered apolipoprotein to plasma in association with high density lipoproteins is proposed. Accompanying the return of filtered apolipoprotein to the plasma is a probable transformation, both in size and composition, of at least some of the lymph high density lipoprotein(2b) and high density lipoprotein(2a) particles into high density lipoprotein3

Relation of hyperlipidemia in serum and loss of high density lipoproteins in urine in the nephrotic syndrome

The mechanism leading to hyperlipidemia in the nephrotic syndrome is not fully understood but may be related in part to loss of high density lipoproteins in the urine of patients with nephrosis. To prove this hypothesis, we compared serum lipoprotein profiles with the excretion of high density lipoproteins in urine in 19 nephrotic patients. Serum cholesterol ranged from 19–152 (median value 45) mg/dl in very low density lipoproteins (VLDL), from 130–443 (median 186) mg/dl in low density lipoproteins (LDL) and from 19–64 (median 33) mg/dl in high density lipoproteins (HDL). Hyperlipoproteinemia was found in 17 patients, which was classified as phenotype IIa (Fredrickson) in 2, as phenotype IIb in 9 and as phenotype IV in 6 subjects. Two patients showed normal lipoprotein patterns. VLDL- and LDL-cholesterol were not found in detectable amounts in urine, whereas HDL-cholesterol was measured in low concentrations from 0.1–8.3 mg/24 h in all samples. There was no correlation between serum HDL-cholesterol and urinary HDL-cholesterol, but a positive correlation between serum LDL-cholesterol and urinary HDL-cholesterol (r= +0.54, p < 0.05). However, the total amount of the daily urinary loss of HDL (<1% of total plasma HDL) seems not to be sufficient to explain hyperlipoproteinemia in the nephrotic syndrome