what is lipid metabolism and how does it work? -SEY PHARMA

The dietary lipids of metabolic significance include triacylglycerol (neutral fat/triglycerides), phospholipids and cholesterol-cholesterol esters.

Digestion and Absorption of Lipid

Some hydrolysis of neutral fat takes place during cooking. A fat splitting enzyme-gastric lipase is present in gastric juice. The activity of this enzyme is restricted as it is sensitive to free acid. Fat hydrolysis in stomach may take place in cases of achylia gastrica and in young suckling ones ingesting large quantities of milk. A small amount of short chain triacylglycerol of milk is digested in the stomach by gastric lipase. However the amount is so slight that it is unimportant.

The pancreatic juice consists of three fat splitting enzymes - pancreatic lipase acting on triacylglycerol, phospholipase A2 which brings about limited hydrolysis of phospholipids at 2 position to form lysophospholipid and cholesterol esterase which causes hydrolysis of cholesterol esters.

The most important enzyme for the digestion of triacylglycerol is pancreatic lipase in pancreatic juice which hydrolyses triacylglycerol in stages. Itactson oil water interface of finely emulsified lipid droplets formed by mechanical agitation in the presence of products of gastric lipase, bile salts, colipase (a protein present in pancreatic juice), phospholipids and phospholipase A2.

The digestion and absorption of lipids occurs in three phases:

Lumen phase :

Pancreatic lipase acts on emulsified fat at position 1 and 3 to form 2-monoacylglycerol (72%) the major end product of triacylglycerol digestion and free fatty acids. By the action of isomerase remaining 2-monoacylglycerol is converted to 1-monoacylglycerol. About 22% of 1-monoacylglycerol is completely hydrolysed to free fatty acids and glycerol.

Absorption of Triacylglycerol-intracellular phase

Short chain fatty acids and glycerol directly pass in portal circulation.

Penetration phase :

The 2-monoacylglycerol, fatty acids (long chain) and small amount of 1-monoacylglycerol leave the oil phase of lipid emulsion and alongwith bile salts, partly hydrolysed phospholipids and free cholesterol form fine droplets-micelles of diameter less than 0.5 u and absorbed into the intestinal epithelium.

Intracellular phase :

Within the intestinal wall 1-monoacylglycerol is further hydrolysed to produce free glycerol and fatty acids by intestinal lipase. Glycerol is reutilised for triacylglycerol synthesis after activation to glycerol 3-phosphate by ATP.

In the intestinal wall 2 monoacylglycerol is reconverted to triacylglycerol via monoacylglycerol pathway. The fatty acids required for resynthesis are first activated.

Lysophospholipids are reacylated with acyl-CoA and cholesterol is esterified. Triacylglycerol, phospholipids and cholesterol esters are packed and generate lipid droplets - chylomicrons, forming a milky fluid chyle that is collected by lymphatics and passed to systemic circulation via thoracic ducts.

Absorption of fat is reduced in pancreatitis, pancreatic insufficiency, malabsorption syndrome and biliary duct obstruction. Steatorrhea is common in these conditions.

Oxidation of fatty acid :

It takes place in three ways:

(a) α-Oxidation :

removal of 1-C atom at a time from the carboxyl end. It is detected in brain tissue.

The enzymes catalysing a-oxidation are located in the endoplasmic reticulum. It does not require CoA intermediates and does not generate high energy phosphates. There is direct hydroxylation of long chain fatty acid at the a-carbon atom to generate a-hydroxy fatty acid which is oxidatively decarboxylated to eliminate one carbon atom from the carboxyl end of the molecule.

α-Oxidation of Fatty acid

Alpha oxidation helps in the oxidation of fatty acids that have a methyl group on β-carbon which blocks β-oxidation. Phytanic acid, derived from phytols, is present in plant foods, contains a methyl group at β-carbon which blocks β-oxidation.

Lipid metabolism disorder

Refsum's disease :

It is a disorder due to genetic defect in the oxidation. The biochemical defect is the lack of a-hydroxylase (phytanic acid oxidase), consequently phytanic acid accumulates in the blood and tissues, resulting into neurological and skeletal abnormalities.

(b) ω-oxidation :

a very minor pathway catalysed by the enzyme monooxygenase (hydroxylase involving cytochrome P450) resulting into the formation of dicarboxylic acid followed by β-oxidation to form adipic and suberic acid which are excreted in urine.

ω-oxidation of fatty acid

(c) Knoop's β-oxidation:

Two carbon atoms are cleaved at a time from acyl-coA starting from carboxyl end. It is the major pathway for the oxidation of fatty acids occurring in mitochondria. Initial step is activation of fatty acid to form acyl-CoA. In this reaction 2 high energy phosphate bonds are expanded. The long chain activated fatty acid requires entry into mitochondria for oxidation, which is facilitated by a special transporter, carnitine (β-hydroxy-γ-trimethylammonium butyrate). Short chain acyl-CoA enters into mitochondria freely.

Role of carnitine in the transport of long chain fatty acid

After the penetration of acyl moiety through mitochondrial membrane via the carnitine transporter system and reformation of acyl-CoA, there follows the removal of 2 hydrogen atoms, catalysed by acyl-CoA dehydrogenase forming Δ²-trans-enoyl-CoA. The coenzyme required is FAD. Water is added to form 3 hydroxyacyl-CoA, Catalysed by the enzyme Δ²-enoyl-CoA hydratase, which undergoes further dehydrogenation on carbon 3 to form corresponding ketoacyl-CoA. NAD is involved as coenzyme. Finally ketoacyl-CoA is split at the 2, 3 position by thiolase involving another molecule of CoA. The products are acetylCoA and acyl-CoA derivative with 2 carbons less than the original acyl-CoA.

β-oxidation of fatty acid

Energetics of Lipid metabolism:

Transport in respiratory chain of electrons from reduced FAD and NAD will form 5 ATP for each of first 7 acetyl-CoA formed by ?-oxidation of palmitate (7 x 5 = 35 ATP). A total of 8 mol of acetyl-CoA is formed and each will give rise to 12 ATP on oxidation in citric acid cycle making 8 mol 12 = 96 ATP. Thus total 131 ATP are formed. Two high energy phosphate bonds are utilised in initial activation of fatty acid. The net production of ATP is 131 - 2 = 129 yielding a net gain of energy (129 x 30.5) 3935 kj/mol of palmitic acid.

Oxidation of unsaturated fatty acid