Lipid Transport & Storage

BIOMEDICAL IMPORTANCE

• Fat – Diet – Synthesized (liver & adipose tissue)

• Transported between the various tissues – Utilization and storage

• Lipids are nonpolar • Lipoproteins • Abnormalities of lipoprotein metabolism

– hypo- or hyperlipoproteinemias – Diabetes mellitus

• Lipids are transported in the plasma as lipoproteins

• Four Major Lipid Classes Are Present in Lipoproteins – Triacylglycerols – Phospholipids– Cholesterol– Cholesteryl esters– free fatty acids (FFA), a much smaller fraction

Major Groups of Plasma Lipoproteins

Lipoproteins consist of a nonpolar core & a single surface layer ofamphipathic lipids

• The Distribution of Apolipoproteins Characterizes the Lipoprotein

• Apolipoproteins roles– form part of the structure of the lipoprotein– they are enzyme cofactors

• C-II for lipoproteinlipase• A-I for lecithin:cholesterol acyltransferase

• Enzyme inhibitors– apo A-II and apo C-III for lipoprotein lipase– apo C-I for cholesteryl ester transfer protein

• act as ligands– apo B-100 and apo E for the LDL receptor

• apo E for the LDL receptor-related protein (LRP), which has been identified as the remnant receptor

• apo A-I for the HDL receptor

FREE FATTY ACIDS

• arise in the plasma from– Lipolysis of triacylglycerol in adipose tissue– action of lipoprotein lipase during uptake of plasma

triacylglycerols into tissues– in combination with albumin

• Levels – low in the fully fed condition– Rise in

• the starved state• diabetes mellitus

FREE FATTY ACIDS

• Oxidized– (fulfilling 25–50% of energy requirements in

starvation)• Esterified– to form triacylglycerol in the tissues

• The free fatty acid uptake– related directly to the plasma free fatty acid

concentration– determined by the rate of lipolysis in adipose tissue.

FREE FATTY ACIDS

• membrane fatty acid transport protein• fatty acid-binding proteins

TRIACYLGLYCEROL

• CHYLOMICRONS– TRANSPORTED FROM THE INTESTINES IN

• VERY LOW DENSITY LIPOPROTEINS– Transport of triacylglycerol from the liver to the

extrahepatic tissues • Intestine and liver– the only tissues from which particulate lipid is secreted

• Apo B is essential for chylomicron and VLDL formation

The formation and secretion of chylomicrons and VLDL

TRIACYLGLYCEROL

• Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver

• Triacylglycerols of Chylomicrons & VLDL Are Hydrolyzed by Lipoprotein Lipase – Lipoprotein lipase – Hepatic lipase

• Concerned with chylomicron remnant and HDL metabolism

TRIACYLGLYCEROL

• Lipoprotein lipase– Phospholipids and apo C-II – apo A-II and apo C-III act as inhibitors – Insulin

• The Action of Lipoprotein Lipase Forms Remnant Lipoproteins– loss of approximately 90% of the triacylglycerol– loss of apo C– apo E, retained– enriched in cholesterol and cholesteryl esters

TRIACYLGLYCEROL

• The Liver Is Responsible for the Uptake of Remnant Lipoproteins

• Uptake is mediated by– A receptor specific for apo E – and both the LDL (apo B-100, E) receptor– and the LRP (LDL receptor-related protein)

Metabolic fate of chylomicrons

• VLDL is the precursor of IDL, which is then converted to LDL

• Two possible fates await IDL– It can be taken up by the liver directly via the LDL

(apo B-100, E) receptor– or it is converted to LDL

LDL

• LDL IS METABOLIZED VIA THE LDL RECEPTOR– LDL (B-100, E) receptor – 30% of LDL is degraded in extrahepatic tissues– 70% in the liver

• Correlation with coronary atherosclerosis

Metabolic fate of VLDL and production of low-density lipoproteins (LDL)

HDL

• Synthesized and secreted from– both liver and intestine

• apo C and apo E are synthesized in the liver and transferred from liver HDL to intestinal HDL when the latter enters the plasma

• Function of HDL– Repository for the apo C and apo E

• Required in the metabolism of chylomicrons and VLDL – TRIACYLGLYCEROL & CHOLESTEROL METABOLISM

Metabolism of high-density lipoprotein (HDL) in reverse cholesterol transport

HDL

• the LCAT system is involved in the removal of excess unesterified cholesterol from lipoproteins and tissues.

• HDL receptor– The class B scavenger receptor B1 (SR-B1)

• reverse cholesterol transport– The smaller HDL3 accepts cholesterol from the

tissues via the ATP-binding cassette transporter-1 (ABC-1).

HDL

• HDL2 HDL3 – after selective delivery of cholesteryl ester to the

liver via the SR-B1– or by hydrolysis of HDL2 phospholipid and

triacylglycerol by hepatic lipase. • Preβ-HDL– is the most potent form of HDL in inducing

cholesterol efflux from the tissues to form discoidal HDL

• HDL concentrations – Vary reciprocally with plasma triacylglycerol

concentrations– Directly with the activity of lipoprotein lipase.

• HDL2 concentrations – Inversely related to the incidence of coronary

atherosclerosis– reflect the efficiency of reverse cholesterol

transport

• THE LIVER plays a central role in lipid transport & metabolism – Facilitates the digestion and absorption of lipids by

the production of bile • has active enzyme systems for– synthesizing and– oxidizing fatty acids– and for synthesizing triacylglycerols and– Phospholipids

• Converts fatty acids to ketone bodies (ketogenesis)

• Plays an integral part in the synthesis and metabolism of plasma lipoproteins

• Hepatic VLDL Secretion– Dietary & Hormonal Status

• Hepatic triacylglycerol synthesis provides the immediate stimulus for the formation and secretion of VLDL.

• The fatty acids used are derived from two possible sources– Synthesis within the liver– Uptake of free fatty acids from the circulation

• during starvation, the feeding of high-fat diets, or in diabetes mellitus

• Factors that enhance both the synthesis of triacylglycerol and the secretion of VLDL by the liver include – the fed state rather than the starved state– the feeding of diets high in carbohydrate – high levels of circulating free fatty acids– ingestion of ethanol– high concentrations of insulin and low concentrations of

glucagon • Enhance fatty acid synthesis and esterification and inhibit their

oxidation

CLINICAL ASPECTS

Metabolism of Acylglycerols& Sphingolipids

CLINICAL ASPECTS

• Raised levels of plasma free fatty acids– Mobilization of fat from adipose tissue– Hydrolysis of lipoprotein triacylglycerol by lipoprotein

lipase in extrahepatic tissues – Imbalance in the Rate of Triacylglycerol Formation & Export

• Causing a fatty liver

• Starvation• High-fat diets• The ability to secrete VLDL may also be impaired • Starvation

CLINICAL ASPECTS

• The second type of fatty liver– Metabolic block in the production of plasma

lipoproteins • Triacylglycerol accumulate

– Block in apolipoprotein synthesis– Block in the synthesis of the lipoprotein from lipid

and apolipoprotein – Failure in provision of phospholipids – Failure in the secretory mechanism

Metabolism of adipose tissue.

• The Provision of Glycerol 3-Phosphate Regulates Esterification

• Lipolysis Is Controlled by Hormone-Sensitive Lipase

• Triacylglycerol is synthesized from acyl-CoA and glycerol 3-phosphate

• Triacylglycerol undergoes hydrolysis by a hormone sensitive lipase to form free fatty acids and glycerol

• there is a continuous cycle of lipolysis and reesterification within the tissue

• Glucose can take several pathways in adipose tissue– Oxidation to CO2 via the citric acid cycle – Oxidation in the pentose phosphate pathway – Conversion to long-chain fatty acid – Formation of acylglycerol via glycerol 3-phosphate

• HORMONES REGULATE FAT MOBILIZATION– Esterification– Lipolysis

• by influencing the activity of the enzymes in the pathways– Hormone-sensitive lipase

• Insulin plays a prominent role in the regulation of adipose tissue metabolism

• The sympathetic nervous system, through liberation of norepinephrine in adipose tissue, plays a central role in the mobilization of free fatty acids

Control of adipose tissue lipolysis

BROWN ADIPOSE TISSUE

• PROMOTES THERMOGENESIS• responsible for diet-induced thermogenesis• The tissue is characterized by a– Well-developed blood supply – High content of mitochondria and cytochromes– Low activity of ATP synthase

• Oxidation and phosphorylation are not coupled in mitochondria of this tissue

• Phosphorylation that does occur is at the substrate level eg,– at the succinate thiokinase step– in glycolysis

• Oxidation produces much heat, and little free energy is trapped in ATP

• Uncoupling protein, thermogenin, acts as a proton conductance pathway dissipating the electrochemical potential across the mitochondrial membrane

Thermogenesis in brown adipose tissue.

Four major groups of lipoproteins

• Chylomicrons transport lipids resulting from digestion and absorption.

• Very low density lipoproteins (VLDL)– Transport triacylglycerol from the liver.

• Low-density lipoproteins (LDL)– Deliver cholesterol to the tissues,

• High-density lipoproteins (HDL) – Remove cholesterol from the tissues in the process

known as reverse cholesterol transport.

• Chylomicrons and VLDL are metabolized by hydrolysis of their triacylglycerol

• Lipoprotein remnants are left in the circulation.• These are taken up by liver• Some of the remnants (IDL) resulting from VLDL

form LDL• LDL is taken up by the liver and other tissues via

the LDL receptor.

Apolipoproteins

• the protein moiety of lipoproteins • act as– enzyme activators (eg, apo C-II and apo A-I)– as ligands for cell receptors (eg, apo A-I, apo E,

and apo B-100).

• Triacylglycerol – The main storage lipid in adipose tissue – Upon mobilization, free fatty acids and glycerol are

released. – Free fatty acids are an important fuel source.

• Brown adipose tissue– Present in small quantity in humans.– the site of “nonshivering thermogenesis – Presence of an uncoupling protein, thermogenin, in the

inner mitochondrial membrane.