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Research Newsletter-Fall/Winter 2008

TRIGLYCERIDE-LOWERING PROPERTIES OF LIPOIC ACID



Régis Moreau, Ph.D.
LPI Assistant Professor (Sr. Res.)

Chronically elevated triglyceride levels in the blood are associated with metabolic syndrome, diabetes, and heart disease. Triglycerides come from the diet and are made in the liver. Obesity, diabetes, a high-fat diet, and various genetic conditions can cause elevated triglycerides. When fed to rats capable of becoming hypertriglyceridemic, lipoic aid, a naturally occurring antioxidant, prevented elevated triglyceride levels and increased HDL (the good cholesterol) levels by over 20%. Lipoic acid apparently works by inhibiting the synthesis of triglycerides in the liver.

The condition of abnormally high blood triglyceride levels (>150 mg/dl) is known as hypertriglyceridemia. Recent estimates indicate that about 30% of U.S. adults have hypertriglyceridemia. Triglycerides (also known as triacylglycerols) are composed of three long-chain fatty acids esterified to glycerol. Animal fats and vegetable oils contain mixtures of triglycerides, which differ by the chain length of their fatty acids and the presence or absence of double bonds in the molecule. Triglyceride is the most concentrated biological fuel—making it an ideal form of energy storage.

There are two main sources of triglycerides: the diet and the liver. Dietary triglycerides are absorbed in the small intestine, assembled into chylomicrons in the intestinal mucosa, and secreted into the lymph. They then enter the blood via the thoracic lymph duct. Muscle and adipose tissues remove some of the triglycerides from the chylomicrons, producing chylomicron remnants that are accumulated in the liver. The liver also produces triglycerides from both fat and carbohydrate. Hepatic triglycerides are then packaged into very low-density lipoproteins (VLDL) and secreted into the blood for delivery to various tissues for the production of energy. Hence, VLDL are the lipoprotein particles formed to transport endogenously derived triglycerides to tissues. Food intake in excess of the body's need for energy exacerbates fat deposition in adipose and muscle tissue, with possible detrimental health consequences.

Hypertriglyceridemia is usually discovered after performing a routine lipid profile. Hypertriglyceridemia stems from disturbances in the synthesis and/or degradation of triglyceriderich lipoproteins and may be the result of various genetic defects and/or a high-fat diet, obesity, diabetes, hypothyroidism, or certain medications. Hypertriglyceridemia is a key component of metabolic syndrome and type 2 diabetes and is also strongly correlated with increased risk of cardiovascular diseases. In its most severe forms, hypertriglyceridemia (500-3,000 mg/dl) may cause pancreatitis, eruptive xanthomas (yellow papules underneath the skin), or lipemia retinalis (creamy white appearance of the blood vessels of the retina).

Conventional therapy for hypertriglyceridemia includes dietary weight loss and exercise, dietary supplementation with fish oil or niacin, and drug intervention, which may include fibrates or combined therapy with statins when low-density lipoprotein (LDL) is elevated (see Table). Although the National Cholesterol Education Program Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of coronary heart disease (for example, hypertriglyceridemic patients at the target level for LDL-cholesterol with low HDL-cholesterol), many physicians remain reluctant to use these drugs due to concerns about muscle dysfunction (myopathy rhabdomyolysis) and the lack of definitive evidence that hyperlipidemia can be controlled with fibrates. As a direct result of these concerns, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) is currently the largest clinical trial ever (10,000 people) to test the efficacy and safety of a fenofibrate/statin combination, with the primary results to be announced in early 2010.

The evidence cited above has led scientists to appreciate the need for complementary therapeutic strategies in the prevention and treatment of hypertriglyceridemia and obesity-induced hyperlipidemia. Recent findings support the novel role of lipoic acid in reducing the metabolic risk factors associated with obesity. Lipoic acid, a naturally occurring antioxidant that serves as a cofactor for mitochondrial enzymes, has long been reported to improve glucose uptake in diabetes and has been prescribed by physicians, especially in Germany. Green leafy vegetables are a good source of lipoic acid. However, the levels needed to exert the metabolic effects discussed here are not commonly achieved dietarily.

Selected therapies for managing hypertriglyceridemia

Although known for its role in glucose uptake, the triglyceride- lowering properties of lipoic acid were only recognized recently. Our studies at the Linus Pauling Institute have contributed to this growing body of knowledge. We added lipoic acid to food fed to Zucker Diabetic Fatty (ZDF) rats, which are used to study hypertriglyceridemia and type 2 diabetes. Typically, ZDF rats become hypertriglyceridemic due to overproduction of triglyceride-rich lipoproteins in the liver, while triglyceride degradation remains normal. When fed a carbohydrate-rich diet, ZDF rats predictably develop hypertriglyceridemia (up to 800 mg triglyceride/dl) at 10 weeks of age and type 2 diabetes (500 mg glucose/dl) at 12 weeks of age. Since ZDF rats are hypertriglyceridemic before becoming fully diabetic, we fed them lipoic acid (2.4 grams per kg of food) from the age of 5 weeks until the age of 10 weeks, thus eliminating potential confounding effects due to diabetes. That dose roughly equates to a daily dose of 2 grams of lipoic acid in humans.

During the course of our experiment, we observed a rise in blood triglycerides (451 mg/dl at 9 weeks of age) in control rats not fed lipoic acid. However, no such increase was detected in the rats fed lipoic acid. We also observed that the rats fed lipoic acid consumed less food than the control rats. Because meal size could affect blood lipid levels, a group of rats was fed a restricted amount of the control diet (without lipoic acid) to match the food intake of the rats fed lipoic acid. This treatment, called pair-feeding, ensures that comparisons between groups are based on the same caloric intake. Despite food restriction, pair-fed rats still developed hypertriglyceridemia (398 mg/dl at 9 weeks of age), indicating that the lipidlowering properties of lipoic acid extend beyond its effect to curb appetite. Hence, subsequent comparisons were made between lipoic acid-fed and pair-fed rats.

In addition to normalizing blood triglycerides, lipoic acid significantly raised high-density lipoprotein (HDL)-cholesterol (the so-called good cholesterol) by 23% with no marked changes in blood total cholesterol. By using the blood triglyceride to HDL-cholesterol ratio as a predictive index of atherogenesis, lipoic acid would decrease the risk for coronary artery disease in ZDF rats by 70%. It is important to remember that these effects of lipoic acid on blood lipids occurred while the ZDF rats were pre-diabetic. Glycemia was not significantly different between experimental groups, nor was glycemia significantly elevated compared to age-matched, lean Zucker rats with normal blood sugar (147 mg glucose/dl).

Next, we identified the triglyceride-rich lipoproteins affected by lipoic acid. Chylomicrons and VLDL are the primary lipoprotein carriers of triglycerides in the blood. Our data showed that lipoic acid decreased circulating VLDL by about 50%, at least in part, by repressing VLDL secretion by the liver. Our data also suggest that lipoic acid lowered blood chylomicrons following a meal. This means that lipoic acid affects triglycerides from both dietary and endogenous origins.

Further analyses of triglyceride synthesis in the liver showed that lipoic acid decreased the gene expression of key enzymes of triglyceride synthesis, namely sn-glycerol-3-phosphate acyltransferase-1 by 81% and diacylglycerol O-acyltransferase-2 by 56%. This result was associated with a decrease in liver triglyceride content by 35% and supports the notion that lipoic acid inhibits liver triglyceride synthesis. Since lipoic acid also decreased the rate of triglyceride-rich VLDL secretion from the liver by 31%, the results further suggest that lipoic acid prevents hypertriglyceridmia by interfering with the liverís ability to synthesize and secrete triglycerides. Because triglyceridemia reflects the balance between triglycerides that are absorbed and synthesized and those that are cleared by peripheral tissues (for example, skeletal muscle, adipose tissue, and heart muscle), we determined whether lipoic acid stimulated the elimination of triglycerides in skeletal muscle. Results obtained thus far suggest that skeletal muscle may be a target tissue for fat elimination in lipoic acid-fed ZDF rats. At the end of the 5-week feeding period, we noted that lipoic acid-treated rats had significantly less perivisceral fat, but their livers were heavier than those of control rats. While a reduction in body fat is certainly seen as positive, the health repercussions of an enlarged liver are uncertain and require further analysis. The anatomical inspection of the livers and measurement of lipid content excluded the possibility of lipoic acid-induced liver steatosis (fatty liver). On the contrary, lipoic acid markedly lowered total lipid concentration by 26% in the liver of ZDF rats, including triglycerides. Moreover, a marker enzyme of liver function (alanine aminotransferase) was normal, indicating that lipoic acid did not cause liver damage. Liver glycogen content was increased by 27% in lipoic acid-fed rats, suggesting that lipoic acid induced the storage of dietary carbohydrates as glycogen instead of being converted into fat. Within certain limits, glycogen deposit is viewed as a healthier alternative to fat deposit. Since glycogen retains significant amounts of water, glycogen and its water content may, at least in part, account for the increase in liver size.

Currently, we are investigating the molecular mechanism of lipoic acid on triglyceride synthesis in rat livers and cultured liver cells. Ongoing studies seek to determine the precise role of known regulatory proteins on key enzymes in the triglyceride synthetic pathway and how lipoic acid may modulate their functions.

In summary, the study showed that the progression of hypertriglyceridemia could be halted by feeding lipoic acid to ZDF rats. Lipoic acid-treated animals were leaner and showed improved blood VLDL- and HDL-cholesterol profiles and a healthier plasma atherogenic index. The inhibition of liver triglyceride synthesis played an important part in the triglyceride-lowering properties of lipoic acid. Since lipoic acid appears to regulate triglyceride metabolism in a manner distinct from prescribed drugs, its mechanism of action should be further investigated. Given its strong safety record in humans, lipoic acid may have promising therapeutic applications against hypertriglyceridemia and hyperlipidemia.

Last updated January 2009