Cholesterol metabolism

While many mechanisms regulate cholesterol homeostasis within the body, limited means of cholesterol input and output exist. Cholesterol input into the body pool is derived from two sources: cholesterol synthesized in the body and cholesterol from the diet. Cholesterol is not an energy-providing nutrient and cannot be broken down by the body. To remove cholesterol from the body, it must be excreted in the form of free cholesterol or bile acids through the liver.

2.3.1 Cholesterol Biosynthesis

The average North American diet provides approximately 300 to 500 mg of cholesterol per day,13 ingested as either free cholesterol or cholesteryl esters. A feedback system exists in which cholesterol synthesis decreases as the ingestion of dietary cholesterol is increased. Endogenous supplies originating from newly synthesized cholesterol, bile, and intestinal mucosal epithelium are about 1000 to 1600 mg/day.14 Synthesis of cholesterol is a multistep process regulated by 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. When an increase in dietary cholesterol occurs, a reduction in hepatic cholesterol synthesis is observed, while synthesis in peripheral tissues may not be altered.15 In this way, hepatic synthesis is the primary regulator of cholesterol balance in the body, despite the human liver accounting for only 10% of whole-body synthesis.16 In hamsters fed a diet containing 2% cholesterol (wt/wt), cholesterol feeding induced hypercholesterolemia and inhibited cholesterol synthesis.17 In addition to feedback inhibition as a result of dietary cholesterol intake, cholesterol synthesis is regulated by other forms of feedback inhibition, hormonal regulation, and sterol-mediated regulation of transcription.18

2.3.2 Cholesterol Absorption

Cholesterol absorption efficiency normally shows great variation among individuals, ranging from 30 to 80% with an average of ~50%.1319 Cholesterol feeding studies have shown that cholesterol absorption efficiency is unchanged up to a relatively large intake of cholesterol, where it reaches a saturation level with poor maximal absorption capacity.1920 Young male Syrian hamsters fed a lithogenic diet containing high cholesterol for 7 weeks showed a reduction in dietary cholesterol absorption efficiency of 26%.21 In rhesus monkeys, cholesterol absorption and fecal excretion are suggested to play a major role in regulating plasma cholesterol concentrations.22 Recently, several transporters have been identified to be involved in cholesterol absorption, including ATP-binding cassette transporters G5 (ABCG5) and G8 (ABCG8) and Niemann-Pick C1 Like 1 (NPC1L1). ABCG5 and ABCG8, transmembrane proteins functioning as a heterodimer, have been shown to play pivotal roles in biliary cholesterol secretion from the liver as well as cholesterol absorption in the intestine.2324 NPC1L1 is required for the intestinal uptake of cholesterol and works as a modulator of whole-body cholesterol homeostasis.25 Because a positive relationship exists between the fractional absorption of cholesterol and plasma cholesterol levels,26 NPC1L1 may be a target for the treatment of hyper-cholesterolemia.27

2.3.3 Cholesterol Transport

With the notable exception of free fatty acids that circulate through the body attached to albumin, lipids are transported in the circulation as a component of lipoprotein particles. A lipoprotein is a spherical particle consisting of a surface monolayer of phospholipids, apolipoproteins, and free cholesterol, and an inner core of triglycerides and cholesteryl esters. The phospholipids are arranged so that their hydrophilic heads are on the outside, allowing the lipoproteins to be dissolved in the circulation. Apolipoproteins, the protein component of lipoproteins, contribute to the regulation of lipoprotein metabolism as well as lipid emulsification. The functions of lipoproteins include maintaining lipid solubility and providing an efficient transport mechanism for lipids in the body.

Several classes of lipoproteins exist, characterized by the various amounts of triglycerides, cholesterol, phospholipids, and protein with which they are composed. The lipoproteins are commonly classified based on their density and are as follows: chylomicrons, VLDLs, low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Individual lipoprotein class exerts differential physiological function in the body.

Chylomicrons are the largest of the lipoproteins and have the lowest density at 0.95 g/ml. As mentioned earlier, a major role of chylomicrons is to transport lipids originating from dietary sources from the small intestine to other tissues and ultimately to the liver. After triglycerides are deposited in peripheral tissues by the action of lipoprotein lipase, the chylomicron remnants are transferred to the liver, where they are endocytosed. As the remnant is hydrolytically degraded, the cholesterol released from the chylomicron regulates the rate of biosynthesis of cholesterol in the liver.

VLDLs, which have a density range of 0.95 to 1.006 g/ml, are produced in the liver and function as transporters for endogenous triglycerides and cholesterol to peripheral tissues.28 The primary apolipoprotein constituents of VLDLs are apolipoproteins B-100, Cs, and E. Apolipoprotein E present in VLDL plays an important role in plasma lipoprotein metabolism through its high binding affinity to cell surface LDL receptors, which could reduce plasma VLDL and LDL concentration as well as the atherosclerotic process.29

After VLDL loses its triglyceride molecules by lipopoprotein lipase primarily in adipose and muscle tissues, the resulting smaller and denser particles become LDL. LDL particles contain a large quantity of cholesteryl esters, and the apolipo-protein constituent is mostly apolipoprotein B-100.30 LDL particles are normally taken up by the liver and extrahepatic tissues, mainly by an LDL receptor-mediated endocytosis.8 LDL receptors are cell surface glycoproteins and their primary function is to take up LDL particles from the circulation in response to cellular cholesterol status.31 In doing so, they maintain cellular cholesterol homeostasis and modulate plasma LDL cholesterol concentrations, ultimately affecting atherogenesis. Once LDLs enter the tissues through these receptors, their components are hydrolyzed, producing cholesterol, amino acids, fatty acids, and phospholipids.

Of the lipoproteins, HDLs contain the highest amount of protein and make up approximately 20 to 30% of the total serum cholesterol. Though numerous apolipoproteins, including As, E, and Cs, are present in HDL particles, apolipopro-teins A-I and A-II represent approximately 80 to 90% of the total apolipoprotein content of HDL. Two clinically defined fractions of HDL exist, i.e., HDL2 and HDL3, which have density ranges of 1.016 to 1.125 g/ml and 1.125 to 1.210 g/ml, respectively. Nascent HDL is produced mainly in the liver and intestine by the function of ABCA1, a cholesterol transport protein that plays a key role in cholesterol and phospholipid efflux.3233 Nascent HDL particles are short-lived in plasma, becoming mature HDL particles when they acquire cholesterol. Lecithin: cholesterol acyltrans-ferase (LCAT) plays a critical role in esterifying free cholesterol from cells, particularly in the extrahepatic tissues, to cholesteryl ester. Numerous studies have shown that HDL protects against cardiovascular disease due, in part, to its participation in reverse cholesterol transport. In this process, excess cholesterol from extrahepatic tissues, including cells in the artery wall, is transported by HDL to the liver for excretion from the body.

2.4 function and effect of lipids 2.4.1 Fats/Saturated Fats and Physical Performance

The impact of fat intake on substrate utilization, exercise training, and performance depends on several factors, including time of ingestion and quantity of fat ingested. Consuming a diet higher in fat prior to exercise has been shown to enhance the body's capacity to oxidize fatty acid.34 However, how diets affect a recovery period after exercise is also important when considering the efficacy of fat intake on physical performance.

Though the benefits of high carbohydrate intake before exercise are well documented, the benefit of a high-fat diet before exercise is not clearly understood. A high-fat/low-carbohydrate diet lowers glycogen stores in the liver and muscle, in part by increasing the utilization of fat stores for energy. While consuming a high-fat/low-carbohydrate diet for a short period of time (1 to 3 days) can actually decrease one's exercise endurance and capacity, a longer period of consumption (>7 days) may enhance fat oxidation during exercise, compensating for the reduced carbohydrate availability. Marked carbohydrate sparing occurs with a longer period of fat adaptation (5 days), with 1 day of carbohydrate intake for glucose normalization without any alteration in exercise performance.3536

As previously mentioned, triglycerides may be stored within striated muscle cells, i.e., IMTG, and provide an important energy source for exercise. At the cellular level, muscle cells have machinery for esterification and hydrolysis of IMTG depending on cellular energy status. As in adipose tissue, when muscle cells have excess energy, fatty acids and glycerols are esterified to form triglycerides for storage, which can be used to supply energy when needed by the cells. Muscle contraction during exercise requires energy so that it triggers hydrolysis of triglycerides primarily by hormone-sensitive lipase, whose products are further metabolized to generate energy.

Given that IMTG is present in muscle cells, it has been presumed that it provides energy to the cells during exercise. However, the degree of contribution of IMTG to exercise as an energy source is still controversial.37 Several factors, including exercise intensity, exercise duration, pre-exercise IMTG level, training status, and gender, can affect use of IMTG during exercise.37 It is likely that IMTG is utilized during moderate-intensity exercise, whereas little or no IMTG is used during low-or high-intensity exercise. During moderate-intensity exercise such as continuous bicycling at 65% VO2 peak, i.e., oxygen uptake peak, the whole-body IMTG oxidation rate reached maximum during the first hour and declined during the second hour of exercise.38 IMTG content in the vastus lateralis muscle decreased at the first 2 hours of bicycle exercise at 60% VO2 without further reduction for 2 hours.39 These studies suggest that IMTG provides energy during an early stage of moderate exercise. Compared with men, IMTG appears to be quantitatively important for women during prolonged moderate-intensity exercise, partly due to higher basal IMTG levels in women than in men.40

Because of the potential role of IMTG as an energy source during exercise, replenishment by post-exercise nutrition, such as increased fat intake, has been explored. Studies have shown that high fat intake (35 to 57% of energy) replenishes IMTG stores faster than low fat intakes (10 to 24%) following prolonged exercise.41,42 With a fat intake of 35% after exercise, IMTG recovery time is only 22 hours.42 A concern exists for the adequacy of replacing glycogen stores by carbohydrate intake when fat intake is substantially increased. It is possible that post-exercise diets moderate in fat will be adequate for repletion of IMTG stores. Additional studies examining fat intake before and after exercise need to be performed to recommend an optimal fat intake to improve athletics' performance.

2.4.2 Cholesterol and Physical Activity

Physical activity has beneficial effects on both plasma HDL cholesterol and triglyceride concentrations as well as LDL and HDL particle size.43 A meta-analysis on the effects of aerobic exercise on lipid profiles of adults at the age of 50 years and older reported that aerobic exercise increased plasma HDL cholesterol, creating a more favorable ratio of plasma total cholesterol to HDL cholesterol concentration.44 The magnitude of increased plasma HDL cholesterol concentration following aerobic exercise training may partially depend on exercise intensity, frequency, duration of the individual exercise session, and the length of the training period. It is suggested that changes in plasma HDL cholesterol levels occur incrementally and reach statistical significance around a distance of 7 to 10 miles of moderate-intensity exercise per week, or equivalent to 1200 to 1600 kcal.45 Resistance exercise has been shown to reduce plasma LDL cholesterol concentration.43

In addition to physical activity independently affecting plasma lipid levels, a combination of interventions, including diet and exercise regimens, has been shown to be effective at positively altering plasma lipid profiles. Decreased saturated fat intake and exercise incorporation induce complementary effects on plasma lipid levels, the combination of which shows a more optimal plasma lipid profile than either intervention alone.46 The modification in dietary lipid intake complements the reduced levels of plasma HDL cholesterol and triglycerides often seen by an increase in physical activity. Therapies involving both a low-saturated-fat diet and exercise incorporation lowered plasma total cholesterol, LDL cholesterol, and triglyceride concentrations by 7 to 18, 7 to 15, and 4 to 18%, respectively, whereas plasma HDL cholesterol concentration was increased by 5 to 14%. Specifically, when diet alone, exercise alone, and a combination of diet and exercise were compared with the control, the diet group (total fat and saturated fat limited to 30 and 7%, respectively) showed the greatest reduction in total cholesterol (7.9%) and LDL cholesterol (7.3%), and the exercise group (trained three times per week for 60 minutes) showed the greatest increases in HDL cholesterol levels (2.3%) and total cholesterol levels (12.2%). The combination group with identically altered diet and exercise as the previous two groups showed favorable results within all four lipid groups.47 The greatest plasma lipid-altering effects have been seen in long-term trials,46 suggesting the significance of the length of treatment to obtain health benefits from diet and exercise intervention.

  1. 4.3 Health Effects of Fat and Cholesterol on Diseases
  2. 4.3.1 Obesity and Diabetes

Obesity, often resulting from chronic excess of dietary energy, is strongly linked to both increased inflammatory status and type 2 diabetes.48 Visceral obesity, dyslipi-demia, and insulin resistance are all conditions that, when they occur simultaneously, comprise what is termed the metabolic syndrome, increasing the risk for both diabetes and cardiovascular disease. Weight loss has been shown to decrease insulin concentration and increase insulin sensitivity.49

Obesity can be influenced by a variety of factors, including genetics, metabolism, environment, and socioeconomic status. Obesity is positively correlated to excess energy intake and low levels of physical activity. In addition, both the degree of total fat consumption and the type of fat consumed play a role in obesity. Dietary fat intake is a significant predictor of sustained weight reduction and progression of type 2 diabetes in high-risk subjects.50 Short-term studies suggest that very high intakes of fat (>35% of calories) may modify metabolism and potentially promote obesity.51 Cross-cultural studies have also shown an increase in body mass index (BMI) in countries with higher intakes of fat.52 In part, the dietary intake of both saturated and total fat is related to the risk of developing diabetes, primarily through its association with a higher BMI.53 An upward trend in overweight has occurred since 1980, including an increase in adults 20 to 74 years of age who are obese, as well as an increase in overweight seen in children. The National Center of Health Statistics reports that the age-adjusted prevalence of overweight increased from 55.9% (1988 to 1994) to 65.1% (1999 to 2002) in adults.54 During this same period, the prevalence of obesity (BMI of 30 or higher) also increased from 22.9% to 30.4%, while extreme obesity (BMI of 40.0 or higher) increased from 2.9% to 4.9%. Modest reductions in total fat intake are suggested to facilitate a decrease in caloric intake, leading to better weight control and potential improvement in metabolic syndrome.55 Coronary Heart Disease (CHD)

Atherosclerosis, the underlying pathological process of CHD, is characterized by an accumulation of plaque and fatty material within the intima of the coronary arteries, cerebral arteries, iliac and femoral arteries, and the aorta. It is the atherosclerotic development in the coronary arteries that leads to CHD and its manifestations. The deposition and buildup of cholesterol and inflammation create reduced blood flow to the heart and possible thrombosis, and are the principle causes of myocardial and cerebral infarction.

Of all cardiovascular diseases, CHD is the leading cause of death for both men and women in the U.S., causing one in five deaths in 2003. Approximately every 29 seconds someone in the U.S. suffers from a CHD-related event, and approximately every minute someone dies from such an event. In addition, it is predicted that 1.2 million Americans will have a new or recurrent coronary attack in 2006, and the estimated direct and indirect cost of CHD for 2006 is $142.5 billion. After the age of 40, the lifetime risk of having coronary heart disease is 49% for men and 32% for women.56 Risks for CHD include both modifiable and nonmodifiable factors, including male gender, increasing age, overweight/obesity, saturated fat intake, and elevated plasma cholesterol levels.

One of the major risk factors for CHD is dyslipidemia, encompassing increases in plasma concentrations of total and LDL cholesterol, along with a decrease in HDL cholesterol concentration. A direct correlation exists between human deaths caused by CHD and plasma cholesterol concentrations.57,58 In particular, a positive correlation between death from CHD and total cholesterol levels exceeding 200 mg/dl prompted the National Cholesterol Education Program to recommend serum cholesterol levels to remain at 200 mg/dl or lower for the general population. Two thirds of CHD-related mortality occurs in individuals who had plasma total cholesterol concentrations higher than 200 mg/dl when they were young adults.58 Between the years of 1999 and 2002, 17% of adults at the age of 20 and more in the U.S. possessed high serum cholesterol levels of 240 mg/dl or higher.54 Elevated plasma LDL cholesterol has been shown to play a major role in the formation of atherosclerotic plaque, making it a common target for prevention strategies.59 According to the 2006 American Heart Association statistical update, approximately 40% of individuals in the U.S. have plasma LDL cholesterol concentrations greater than 130 mg/dl, above the recommendation for individuals with a moderate risk (two or more risk factors and a 10-year risk of developing CHD of <10%) or moderately high risk (two or more risk factors and a 10-year risk of developing CHD of 10 to 20%).60 The risk of CHD falls as concentrations of plasma HDL cholesterol increase, especially to levels of >40 mg/dl.

Contrary to previous beliefs, altering the amount of cholesterol ingested has only a minor effect on total plasma cholesterol concentration in most people. A study performed on over 80,000 female nurses found that increasing cholesterol intake by 200 mg for every 1000 calories in the diet did not appreciably increase the risk for heart disease.61 Because the body is well equipped with compensatory mechanisms to maintain cholesterol homeostasis, if a decrease in dietary cholesterol intake occurs, the biosynthesis of cholesterol increases, almost to a level to fully compensate for the decrease in cholesterol intake; in contrast, when body has excess cholesterol, cholesterol biosynthesis decreases with a concomitant increase in cholesterol excretion pathways through biliary cholesterol and bile acids.

Plasma cholesterol concentrations are more subject to regulation by dietary fat than dietary cholesterol. As previously noted, short-term studies indicate that very high intakes of fat (>35% of calories) may have the ability to modify metabolism and potentially promote obesity.51 The Women's Health Initiative Dietary Modification Trial, a long-term dietary intervention study on approximately 49,000 women, was designed to investigate the effect of dietary intervention on the risk of cancer and CHD. The 8.1-year follow-up showed trends toward greater reductions in CHD risk, i.e., reduction in LDL cholesterol levels in individuals consuming lower intakes of saturated fat (2.9% decrease by year 6), but found nearly identical rates of heart attacks, strokes, and other forms of cardiovascular disease.62 Findings from the study are similar to both the Nurses' Health Study and the Health Professionals Follow-Up Study, indicating no link between the overall percentage of calories from fat and several health outcomes, including cancer, heart disease, and weight gain.

A majority of saturated fatty acids appear to have a negative effect on plasma cholesterol profiles, i.e., increases in LDL cholesterol level and LDL:HDL ratio and a decrease in HDL cholesterol level, which can enhance the risk of CHD. Hyper-cholesterolemic effects of saturated fatty acids are attributed, in part, to their abilities to alter the secretion of bile acids, to regulate gene expression, to enhance LDL formation, and to inhibit the reverse cholesterol transport pathway by retarding the activity of lecithin:cholesterol acyltransferase, a plasma protein important for reverse cholesterol transport pathway. Therefore, recent clinical trials replacing saturated fatty acids with monounsaturated fatty acids showed an improvement in plasma lipid profiles, as well as beneficial effects on insulin sensitivity.63-65 Decreasing saturated fat intake from 12% to 8% has been shown to decrease plasma LDL cholesterol by 5 to 7 mg/dl, based upon equations from Hegsted et al.66 and Mensink and Katan.67 While most of the saturated fatty acids, such as lauric (12:0), myristic (14:0), and palmitic (16:0) acids, are all considered hypercholesterolemia researchers have shown that stearic acid (18:0) actually has a neutral or mild hypocholesterolemic effect on plasma total and LDL cholesterol.68-73 In addition, 18:0 was as effective as 18:1 in lowering plasma cholesterol levels when it replaced 16:0 in the diet.74

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