Lipotropic Agents Yusuf Saleeby, MD
Introduction & definition
A lipotropic agent is a compound that removes or inhibits the deposition of lipids (fats) in organs, specifically the liver. With recent weight management programs and the resurgence of the controversial hCG protocol for weight loss, lipotropic agents like the MIC (Methionine, Inositol & Choline) injection and Betaine are coming back into the limelight. To better understand the use of these agents as potential weight loss compounds we must understand the physiology and pharmacology behind lipotropics (Frame, 1942).
During the early 1930’s, the properties of lipotropic agents were elucidated predominantly by the work of Dr. Charles H. Best, a researcher in the field of liver disease and lipid chemistry. There was intense interest in lipotropics with regard to treating particular liver disorders as one perceives with the many peer reviewed medical journal citings during 1930’s and into 1950’s. The focus was on the treatment of fatty liver disease, a problem where lipids accumulate in the hepatic cells. In 1954, Dr. Albert Simeons published work on the use of a female hormone called hCG (human Chorionic Gonadotropin) in a protocol for significant weight reductions in obese patients (Asher, 1974; Bosch, 1990). Today this protocol is again gaining much notoriety, even in a revised format and with the aid of utilizing lipotropic agents. Alcoholic fatty liver disease was noted to exist as early as the 1800’s and agents were desired to help remove triglyceride or fat collections that poisoned the liver from overconsumption of alcoholic beverages. Non-alcoholic fatty liver disease, a fairly benign process at its onset was eventually recognized to lead to a more worrisome disorder called NASH (Non-Alcoholic Steatohepatitis) in the 1980’s at the Mayo Clinic (Vuppalanchi, 2009). Both non-alcoholic fatty liver and NASH are due primarily to obesity, dysglycemia (diabetes) and hypertriglyceridemia (elevated triglycerides).
A weight loss management program should not be of such narrow focus to just drop unsightly fat from our bodies, but rather include loss of visceral and organ fat as well. That is where lipotropic agents come into play. Not only may they be useful in mobilizing fats for weight loss, but they help in reversing the detrimental lipid build up in organs, especially the liver that can lead to disease and illness.
The lipotropic agent Betaine (trimethylglycine, TMG) is an example of an orally administered compound having dual functions as an osmolyte to protect cells, proteins and enzymes from environmental stress as well as being methyl group donors. Betaine is a natural extract from sugar beets and is derived from choline. An important function of betaine is to increases liver glutathione levels while lowering homocysteine concentrations. Betaine is able to synthesize l-methionine from the amino acid homocysteine. Biochemically it participates in the methionine cycle in the liver and kidneys as a methyl donor and neutralizer of free radicals and hydroxyl groups. Inadequate methyl group levels can lead to hypomethylation in important enzymatic pathways that affect hepatic proteins. This methyl group deficiency can result in elevated plasma homocysteine concentrations (know as an independent risk factor for coronary disease and stroke) and it can also result in inadequate fat metabolism leading to steatosis or fatty liver disease. With inadequate bethaine consumption in our diet, the result is serum lipid abnormalities or dyslipidemia (Craig, 2004).
Choline is a water-soluble essential nutrient and lipotropic agent often grouped with the B-family of vitamins. Choline protects the liver against environmental toxins and poisonings. One way choline protects the liver is by detoxifies amines, a byproduct of protein metabolism. In one experiment liver cells were rescued with doses of choline in an intentional poisoning with carbon tetrachloride in laboratory animals (Barret, 1939). In our diet the best source of choline is lecithin also known as phosphatidylcholine (Shils, 1999). Lecithin is found naturally in egg yolk and soy beans. Choline goes through an oxidative process converting it to the metabolite betaine, itself the potent lipotropic and free radical scavenger. When we consume fat and lipids and they are absorbed in our alimentary tract, from there they are transported through the bloodstream to the liver in chylomicrons, a type of lipoprotein. Within the liver these fats and cholesterol are packaged into very low density lipoproteins (VLDL) for transportation thorough blood to tissues that need them. Phosphatidylcholine or choline is a component of this transport VLDL particle and without it the fat and cholesterol would accumulate in a negative way in the liver. Making sure there are no choline deficiencies in our diet or even making available larger doses of choline insures us of mobilizing fat out of the liver and back into circulation to be used for fuel or other purposes by cells.
Dietary cholesterol was shown in experiments to slow down phospholipid turnover in the liver. Conversely, choline and betaine were shown by researchers Dr. Andrew J. Perlman and Dr. I. L. Chiakoff to speed up phospholipid metabolism within an hour after choline ingestion. The choline effects of mobilizing fats appear to linger for up to 12 hours after consumption (Perlman, 1939). Diets high in refined grains (low in whole grain breads for example) have a relative deficiency in both betaine and choline. This is another reason why whole grains are preferred over refined or processed grains. Besides the lipid effects, low levels of dietary choline and betaine lead to elevated homocysteine levels and their untoward effects on the cardiovascular system (Ryan, 2007).
It is noteworthy that the mitochondrial enzyme carnitine palmitoyltransferase-1 (CPT-1) is responsible for fatty acid metabolism and is the rate-limiting step of the fatty acid oxidation pathway making it of interest in the treatment of obesity. Researchers feeding high fat and choline-betaine deficient diets to laboratory animals noticed an increase in NASH with an inactivation or oxidation of the CPT-1 mitochondiral enzyme activity (Serviddio, 2011). Modulation and manipulation of CPT-1 may affect energy metabolism and food intake, and research is ongoing into the effects of both stimulation and inhibition of CPT-1 and its relationship to obesity management (Kuhajda, 2007).
In 1937 Dr. Helen Tucker and Dr. H. C. Eckstein determined methionine to be a lipotropic agent. The experiments of Dr. Charles Best and Dr. Jessie Ridout showed that even small doses of methionine have the same effect on fat metabolism as higher doses (Best, 1940; Tucker, 1937). Methionine is an essential amino acid that helps the body take control of excessive serum levels of estrogen for one thing. High estrogen levels reduce bile concentrations that are responsible for fat emulsification and lipid passage through the liver. Methionine helps deactivate estrogens leading to improved fat metabolism and mobilization. It is well noted that elevated estrogen levels, especially in males lead to unsightly adipose depositions and obesity. Overweight men have issues with feminization as their estrogen levels tend to climb. Methionine along with choline detoxifies amines in protein metabolism. It also acts as a catalyst for choline and inositol functions. Methionine has another important function in that it affects the body’s levels of glutathione. Glutathione is a compound in the liver that is crucial in hepatic detoxification and acting as a very potent antioxidant. Glutathione is essential for the defense of the liver against toxic compounds that it metabolizes after oral ingestion. Glutathione is essential for good health and while oral intake of glutathione does nothing to embellish its liver concentrations, it is indispensable for that process to occur with intake of substrates or precursor components. Besides methionine and choline; n-acetylcysteine (NAC) and the amino acids glutamine and glycine are of importance (Shils, 1999).
Inositol also known as myo-inositol, is a lipotropic agent who action prevents the trapping of fat in the liver. Inositol is a compound classified as a carbohydrate, although not a classic sugar as we would recognize. It is found naturally in nuts, beans, melons and oranges as a dietary source. Once considered a member of the vitamin B-complex family, is was determined to be synthesized from glucose and thus lost the ‘’vitamin’’ title as an essential nutrient. However, inositol does have an vital role in human health (Giordano, 2011). Inositol and choline together prevent cholesterol from sticking to the arterial walls and inositol helps with the transport of fat through the blood stream (Rapiejko, 2986). In a scientific study it was demonstrated that choline exhibits more of a lipotropic effect than does inositol in both laboratory animals fed fat-free and fat containing diets (Best, 1951). Not to detract from the importance of inositol, it should also be noted that lipotropics tend to work in synergy with one another. Heavy consumption of caffeine can deplete inositol stores, and this may be one facet of how caffeinated beverage consumption today is leading to obesity and dysmetabolism. While each of these lipotropic agents act alone as a fat mobilizing compound, they are all related and interdependent upon each other in one fashion or another. Often times the effects of lipotropics are symbiotic if not embellished by the others presence. It is very reasonable to co-administer two or more of these agents for best effect.
Use Today in Weight Loss and Health
Today as an adjunct to good nutritional counseling and appropriate dietary protocols for reductions in weight and adipose tissue, lipotropic agents can be used by doctors and nutritionists to help patients lose and control their weight. Lipotropic agents certainly have their place among important nutraceutical considerations for weight management protocols. Both oral and intramuscular administration of lipotropics can aid in the reductions in weight and maintenance of those suffering from obesity, diabetes, and metabolic syndrome (D'Anna, 2011; Rapiejko, 1986). A very common lipotropic “cocktail” is the MIC (methionine, inositol and choline) which is injection into deep muscle usually on a weekly basis. Orally administered betaine (TMG) can be taken as an alternative to the injected forms of the MIC preparation having similar effects in most cases. There are few contraindications to the use of these lipotropic agents in moderation as they do occur in healthy diets naturally, however, super physiological doses should be administered under the careful supervision of a physician.
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