Triglycerides as energy stores:

Fats, in the form of triglycerides, are an ideal energy storage form because: a. they are highly reduced and b. they are anhydrous (by contrast, glycogen is 1 part carbohydrate and 2 parts water).

A 70 kg person stores about 60 days-worth of energy or 400,000 kJ in triglycerides (37 kJ/g), whereas, this person stores only 1 days-worth of energy or 2,500 kJ as glycogen (17 kJ/g).

A reflection of the central position of fat in animal's energy storage strategy is the fact that a special cell-type, the adipocyte (or fat cell) is dedicated to the storage of triglycerides. This cell consists of a nucleus, a cell membrane, and triglycerides.

Digestion and Absorption:

The lipid portion of the human diet consists largely of triglycerides and cholesterol (and its esters). These must be emulsified, and digested to be absorbed according to the following outline:

a. fats (triacylglycerols) are ingested

b. bile (bile acids, salts, and cholesterol), which are made in the liver, are secreted by gall bladder

c. pancreatic lipase digests the triglycerides to fatty acids, plus di-, and mono- acylglycerols

d. these are absorbed by intestinal epithelial cells and resynthesized into triacylglycerols once inside the cells

e. these triglycerides and some cholesterol are combined with apolipoproteins to produce chylomicrons (these are approximately 95% triglycerides)

f. the chylomicrons transport fatty acids to peripheral tissues; any excess fat is stored in adipose tissue

Lipoprotein Metabolism

Since the triglycerides, cholesterol esters, and cholesterol absorbed in the small intestine are not soluble in aqueous medium, they must be combined with suitable proteins (apolipoproteins, which are shown in parenthesis below) in order to prevent them from forming large oil droplets. The resulting lipoproteins undergo a type of metabolism as they pass through the bloodstream and certain organs (notably the liver). Events in this process are outlined below:

Intestine --> chylomicrons (containing the apoproteins C-2, C-3, and E) ---> capillaries --->

digested to remnants ----> liver ----> VLDL (B-100, C-2, C-3, E) ---> capillaries --->

IDL (B-100, E) ----> liver ---> LDL (B-100) ----> absorbed by peripheral tissues (see LDL receptor model below).

Also synthesized in the liver is high density lipoprotein (HDL), which contains the apoproteins A-1, A-2, C-1, and D; HDL collects cholesterol from peripheral tissues and blood vessels and returns it to the liver.

The LDL Receptor model

Brown and Goldstein began the study of familial hypercholesterolemia in middle 1972; by 1985 they had been awarded the Nobel prize for their model of low density lipoprotein (LDL) metabolism.

They examined the following observations:

a. individuals who are homozygous recessive (rr) for the LDL receptor have very high serum cholesterol levels (in the range of 650-1000 mg/dl); they usually die of heart attack by age of 20.

b. individuals who are heterozygous (Rr) for the LDL receptor gene have about half the normal level of receptors and have serum cholesterol levels of 250-500 mg/dl. They tend to have heart attacks in their thirties and forties.

c. individuals who have normal serum levels (160-200 mg/dl) are homozygous dominant (RR).

The model:

a. LDL is taken up by specific cell surface receptors (these come together to form coated pits)

b. LDL is taken in as an endosome, which fuses with a lysosome (here, cholesterol ester is converted to free cholesterol)

c. the apoproteins (apo B-100) are digested to amino acids

d. the receptor protein is recycled to the cell membrane

e. the free cholesterol that was formed has two fates:

1. moves to endoplasmic reticulum, where

a. inhibits HMG-CoA reductase

b. inhibits the synthesis of HMG-CoA reductase

c. speeds up the degradation of HMG-CoA reductase

d. inhibits the synthesis cell surface receptors for LDL

2. is converted, by acyl-CoA, acyl transferase (ACAT), to cholesterol esters, which form oil droplets

Fat mobilization:

Mobilization of fat is stimulated in a manner similar to the acceleration of glycogen breakdown.

A hormone (epinephrine or glucagon) binds to a receptor in the cell membrane; this process activates an adenylate cyclase. The following sequence of reactions takes place:

a. cAMP activates a protein kinase by causing the dissociation of the regulatory subunits (R2C2 ----> 2 C).

b. the protein kinase phosphorylates the triacylglycerol lipase, which leads to digestion of triglycerides and the release of free fatty acids.

c. the fatty acids pass into the bloodstream, where they bind to with serum albumin.