Gugulipid® -
Mechanism(s) of Action
The studies on gum guggul indicate that
its hypolipidemic activity can be attributed to more than one mechanism.Some of the
possible mechanisms include:
1. Inhibition of cholesterol
biosynthesis,
2. Enhancing the rate of excretion of cholesterol,
3. Promoting rapid degradation of cholesterol,
4. Thyroid stimulation,
5. Alteration of biogenic amines
6. High affinity binding and anion exchange.
The first 3 mechanisms, inhibition of
cholesterol biosynthesis, enhancing rate of excretion of cholesterol, and promoting rapid
degradation of cholesterol, are related in that the end result is the elimination of
cholesterol. Cholesterol is an ubiquitous and important compound that is an essential
component of mammalian cell membranes. It is a precursor of bile acids, steroid hormones,
and vitamin D. Since cholesterol is readily synthesized in most tissues of the human body,
it is not a dietary essential. In normal human adults, the largest amounts of cholesterol
are found in the liver (0.3%), skin (0.3%, related to vitamin D formation), brain and
nervous tissue (2.0%), intestine (0.2%) and certain endocrine glands (related to steroid
hormone biosynthesis, adrenal glands contain approx. 10%). Approximately 50% of the myelin
sheath (surrounds and insulates nerves) is cholesterol that is related to proper nerve
conduction and normal brain function. It has been estimated that a 71 kg adult male has
approximately 75 to 150 g of cholesterol in his body.
Nearly 50% of the cholesterol produced
daily is converted to bile acids and secreted as bile salts in bile. Most of it is
reabsorbed and reused via enterohepatic circulation. A portion of the cholesterol that
remains (approx. 0.5 to 1 g) is used to form the steroid hormones, cell membranes, and
vitamin D in the skin. Any excess cholesterol is excreted mainly in the bile and
intestinal tract. Also, a small amount is excreted via the skin as desquamated cells,
sweat, and sebaceous secretions.
Figure
1. Factors that influence the turnover of cholesterol in the body
Inhibition of cholesterol biosynthesis
Gugulipid®
markedly inhibits liver cholesterol biosynthesis. This causes interference in lipoprotein
formation and lipid turnover.
Cholesterol is primarily biosynthesized in the
liver and the intestine and transported to the peripheral tissues in the form of
lipoproteins. Lipoproteins are the only tissues that manufacture apolipoprotein B, the
protein component of LDL and VLDL that are both cholesterol transport proteins. The
rate-limiting step in cholesterol biosynthesis is the reduction of HMG-CoA to mevalonic
acid by HMG-CoA reductase. Cholesterol controls its own formation by inhibiting this step
(feedback inhibition).
Figure
2. Cholesterol Biosynthesis
Enhancing rate of excretion of cholesterol
Gugulipid® increases fecal
excretion of bile acids (cholic and deoxycholic acids) and cholesterol. This indicates a
low rate of absorption of fat and cholesterol in the intestine.
In a normal, healthy adult following a
low cholesterol diet, cholesterol (1300 mg) is returned to the liver to be disposed of
each day (enterohepatic recirculation). The liver disposes off cholesterol by
1. excretion in the bile as free cholesterol where it is
converted to
bile salts,
2. esterification and storage in the liver as cholesterol esters,
3. and incorporation into VLDL and LDL (lipoproteins) and secretion
into the circulation.
The primary bile salts include taurocholate,
taurochenodeoxycholate, glycochenodeoxycholate, while the secondary ones are deoxycholate
and lithocholate.
Figure 3.
Promoting the rapid degradation of cholesterol
Gugulipid® stimulates the LDL
receptor binding activity in the liver membrane, and its hypolipidemic activity is due to
rapid catabolism (degradation) of LDL.
Cholesterol biosynthesis may be
suppressed by LDL-bound cholesterol. This involves specific LDL receptors that project
from the surface of human cells. The first step in regulating cholesterol biosynthesis is
binding of the lipoprotein LDL to these LDL receptors. As a result, the LDL particles are
extracted from the blood. Saturability, high affinity, and a high degree of specificity
characterize the binding reaction. Only LDL and VLDL are recognized by the LDL receptors.
(They both contain apolipoprotein B-100.) The cholesterol lipoprotein is endocytosed as
clathrin-coated vesicles when binding occurs at sites on the plasma membrane that contains
pits coated with clathrin (a protein). Once this occurs, the coated vesicle loses its
clathrin and becomes an endosome intracellularly. This process is known as
receptor-mediated endocytosis. The second step involves fusion of the endosome with a
lysosome that contains hydrolytic enzymes (proteases and cholesterol esterase). The LDL
receptor separates from LDL and returns to the surface of the cell. Inside the lysosome
LDL’s cholesterol esters become hydrolyzed by cholesterol esterase. Subsequently,
free cholesterol and a long-chain fatty acid are produced. The free cholesterol diffuses
into the cytoplasm where it inhibits the activity of HMG CoA reductase. Thus, it
suppresses the synthesis of HMG CoA reductase. Simultaneously, fatty acyl CoA:cholesterol
acyltransferase (ACAT) is activated by cholesterol and promotes the formation of
cholesterol esters, primarily cholesterol oleate. The accumulation of the intracellular
cholesterol eventually inhibits replenishment of LDL receptors on the cell ‘s
surface, and this causes blocking of further cholesterol take and accumulation.
Reducing lipid peroxides
The protective, antioxidant properties of
Gugulipid® may also play a part in its lipid lowering activity. It reduces
lipid peroxides, xanthine oxidase, and increases superoxide dismutase.
Thyroid Stimulation
The lipid lowering properties of
Gugulipid® may be due to its ability to increase thyroid hormone production.
Thyroid hormones control the metabolic
rate of the entire body. Thyroxine (T4) and the more active triiodothyronine (T3)
are the two most important hormones. Both T4 and T3 are present in
tissue cells. They enter them by diffusion. Thus, the thyroid affects most tissues (e.g.
cardiovascular system, gastrointestinal system, and muscular activity). Thyroid hormones
provide many essential functions. They increase the metabolism of carbohydrates, enhance
protein synthesis and stimulate the use and breakdown of lipid (fats).
Figure 4
Alteration of Biogenic Amines
Preclinical studies have reported
gugulipid’s effect on biogenic amines, catecholamine and dopamine b-hydroxylase
activity. This may attribute to its lipid lowering properties.
Gugulipid (100 mg/kg dose) significantly
increased catecholamine levels and dopamine b-hydroxylase
activity in normal rabbits. (Dopamine b-hydroxylase activity
and catecholamine levels were decreased in cholesterol (500 mg/kg dose) fed rabbits.
Gugulipid is noted for helping the hypercholesterolemic rabbits to recover the decrease in
catecholamine synthesis.)
Gugulipid (50, 120, and 240 mg/kg doses)
increased the levels of norepinephrine and dopamine and dopamine b-hydroxylase
activity of the brain and heart tissues of rhesus monkeys’ in a dose-dependent
manner.
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