BIOMEDICAL / CLINICAL CONCEPTS

An adult human body contains about 10-11 kg of fat reserve corresponding to about 100,000 Cal. This can meet the energy requirements for several weeks of food deprivation in man. The sudden infant death (SIDS)an unexpected overnight death of healthy infantsis attributed to a blockade in -oxidation of fatty acids, caused by a deficiency o fmedium chain acyl CoA dehydrogenase (MCAD). Jamaican vomiting sickness is due to consumption of unripe ackee fruit containing hypoglycin A which blocks -oxidation. Methylmalonic acidemia occurs either due to a deficiency of the vitamin B12 or a defect in an enzyme methyl malonyl CoA mutase. This disorder retards growth and damages central nervous system. Zellweger syndrome is caused by absence of peroxisomes in tissues; as a result, the long chain fatty acids cannot be oxidized. Refsums disease is due a defect in -oxidation of fatty acids. The patients are advised not to consume diets containing chlorophyll.

BIOMEDICAL / CLINICAL CONCEPTS

Ketosis is commonly associated with uncontrolled diabetes mellitus and starvation. Diabetes ketoacidosis is dangerousmay result in coma or even death. Starvation, however, is not accompanied by ketoacidosis. Insulin promotes fatty acid synthesis by stimulating the conversion of pyruvate to acetyl CoA. The lack of the ability of the organisms to introduce double bonds in fatty acids beyond C9 and C10 makes linoleic and linolenic acids essential to mammals. Niemann-Pick disease, caused by a defect in the enzyme sphingomyelinase, results in the accumulation of sphingomyelins in liver and spleen. About a dozen glycolipid storage disease are known. These include Gauchers disease and Krabbes disease.

BIOMEDICAL / CLINICAL CONCEPTS

Hypercholesterolemia is associated with atherosclerosis and coronary heart diseases. Consumption of polyunsaturated fatty acids and fiber decreases cholesterol in circulation. Drugssuch as lovastatin, cholestyramine, compactin and clofibratereduce plasma cholesterol. Cholelithiasis, a cholesterol gall stone disease, is caused by a defect in the absorption of bile salts from the intestine or biliary tract obstruction. High density lipoproteinsin association with lecithin-cholesterol acyltransferase (LCAT)are responsible for the transport and elimination of cholesterol from the body. Hyperlipoproteinemias are a group of disorders caused by the elevation of one or more of plasma lipoprotein fractions. Excessive accumulation of triacylglycerols causes fatty liver which can often be prevented by the consumpiton of lipotropic factors (choline, betaine, methionine).

BIOMEDICAL / CLINICAL CONCEPTS

Obesity is an abnormal increase in body weight due to excessive fat deposition (>25%). Overeating, lack of exercise and genetic predisposition play a significant role in the development of obesity. Some individuals with active brown adipose tissue do not become obese despite overeating, since whatever they eat is liberated as heat due to uncoupling of oxidation and phosphorylation in the mitochondria. A protein namely leptin, produced by the adipose tissue, has been identified (1994) in mice. Injection of leptin to obese mice caused reduction in body fat, increased metabolic rate and increased insulin concentration, besides reduced food intake. Leptin has also been detected in humans. Anorexia nervosa is a psychiatric disorder associated with total loss of appetitemostly found in females in the age group 10-30 years.

BIOMEDICAL / CLINICAL CONCEPTS

Atherosclerosis is characterized by hardening of arteries due to the acccumulation of lipids and other compounds. The probable causes of atherosclerosis include hyperlipoproteinemias, diabetes mellitus, obesity, high consumption of saturated fat, lack of exercise and stress. Atherosclerosis and coronary heart disease are directly correlated with plasma cholesterol and LDL, inversely with HDL. Elevation of plasma lipoproteina suggests increased risk of CHD. Alcoholism is associated with fatty liver, hyperlipidemia and atherosclerosis.

SUMMARY
1. Triacylglycerols (TG) are the highly concentrated form of energy, stored in adipose tissue. Hormone-sensitive lipase hydrolyses TG to free fatty acids which are transported as albumin-FFA complexes. 2. Fatty acids are activated (acyl CoA) and transported by carnitine to mitochondria where they get oxidized (mostly type) to liberate energy. Complete oxidation of one mole palmitate liberates 129 ATP. 3. Excessive utilization of fatty acids occurs in uncontrolled diabetes mellitus and starvation. This results in the overproduction of ketone bodies (in liver), namely acetone, acetoacetic acid and hydroxy butyric acid. The last two ketone bodies serve as energy source for peripheral tissues. 4. Fatty acid biosynthesis occurs from acetyl CoA in the cytosol through the involvement of a multienzyme complex associated with acyl carrier protein (ACP). The reducing equivalents (NADPH + H+) are supplied mostly by HMP shunt.

SUMMARY
5. Synthesis of triacylglycerols and phospholipids (PL) occurs from glycerol 3-phosphate and dihydroxyacetone phosphate with the addition of acyl CoA, and activated nitrogenous bases (for PL). 6. Cholesterol is synthesized from acetyl CoA in a series of reactions involving HMG CoA, mevalnate, isoprenoid units and squalene as the intermediates. Cholesterol serves as a precursor for bile acids, steroid hormones and vitamin D. 7. Lipoproteins are the transport vehicles for lipids in the plasma. Lipoprotein disorders are associated with abnormalities in their plasma levels. Elevation in LDL and VLDLin association with cholesterol and TGposes a serious health problem with increased risk of atherosclerosis and CHD. 8. Excessive accumulation of triacylglycerols in liver causes fatty liver, which may be due to increased production of TG or impairment in lipoprotein (VLDL) synthesis. The latter is mostly associated with the deficiency of certain substances called lipotropic factors (e.g. choline, betaine, methionine, etc.).

SUMMARY
9. Obesity is an abnormal increase in body weight (with more than 25% due to fat). Among the many causative factors of obesity, lack of active brown adipose tissue (which burn fat and liberate heat) in these individuals is gaining importance. 10. Atherosclerosis is a complex disease characterized by thickening of arteries due to the accumulation of lipids. Atherosclerosis and CHD are directly correlated with LDL and inversely with HDL of plasma.

SELF-ASSESSMENT EXERCISES
Fill in the blanks. 1. The most predominant lipid component of chylomicrons _________________. 2. Cholesterol synthesis is controlled by feedback inhibition of the enzyme _________________. 3. A compound possessing hydrophobic and hydrophilic groups in its structure is known as __________________. 4. Niemann-Pick disease is due to a defect in the enzyme ________. 5. The lipoprotein involved in the reverse cholesterol transport is _______________. 6. The total number of ATP produced by the oxidation of a molecule of palmitic acid is ______________. 7. The long chain fatty acids (C26C35) are not oxidized due to the absence of peroxisomes. This disorder is known as ___________.

SELF-ASSESSMENT EXERCISES
8. Acetyl CoA from the mitochondria is transported into the cytosol after its conversion to _______________. 9. Plasma lipoprotein that is inversely correlated with coronary heart disease is _______________. 10. The fatty acid that is commonly found in the C2 of triacylglycerols is _________________. Multiple choice questions. 11. The following substance is ketogenic a) Fatty acids b) Leucine c) Lysine d) All of them 12. The lipoprotein possessing the highest quantity of phospholipid a) HDL b) LDL c) VLDL d) Chylomicrons 13. Hypercholesterolemia is observed in the disorder
a) Hypothyroidism b) Diabetes mellitus c) Nephrotic syndrome d) all of them

SELF-ASSESSMENT EXERCISES
14. The two final products in the -oxidation of odd chain fatty acids are a) Acetyl CoA and malonyl CoA b) Acetyl CoA and acetyl CoA c) Acetyl CoA and propionyl CoA d) Acetyl CoA and succinyl CoA 15. Hormone sensitive lipase activity is inhibited by the hormone a) Epinephrine b) Insulin c) Thyroxine d) Glucocorticoids