Plasma Lipid Transport Role of HDL Philip Barter, MBBS, FRACP, PhD Professor and Director The Heart Research Institute, Sydney, Australia

Plasma Lipid Transport Liver FC CE TG FFA Adipose tissue CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids TG: triglycerides Cholesterol of dietary origin is taken up by the liver where it combines with cholesterol newly synthesised in the liver. This cholesterol is subsequently esterified. Triglyceride is formed in the liver either from newly synthesis fatty acids or from free fatty acids (FFA) released from adipose tissue. The cholesteryl esters and triglyceride are incorporated into VLDL.

Plasma Lipid Transport Liver VLDL TG FC CE TG CE FFA Adipose tissue CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids TG: triglycerides The VLDL (and the cholesterol they contain) are subsequently secreted into plasma.

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues FFA Adipose tissue CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LPL: lipoprotein lipase TG: triglycerides Once in plasma the triglyceride in VLDL is broken down by lipoprotein lipase, releasing free fatty acids for uptake by tissues.

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues LDL FFA TG TG Adipose tissue CE CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LPL: lipoprotein lipase TG: triglycerides As it loses its triglyceride, the VLDL particle becomes progressively smaller and, in a complex series of reactions, is ultimately converted into a triglyceride-poor, cholesterol-rich LDL particle.

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues LDL FFA TG LDL receptor TG Adipose tissue CE Liver LDL receptor CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LPL: lipoprotein lipase TG: triglycerides The cholesterol in LDL is subsequently delivered to tissues following binding of the particles to LDL receptors. Since the level of expression of the LDL receptor is increased in cells that are depleted of cholesterol and decreased in cells that are overloaded with cholesterol, this process ensures that the cholesterol in LDL is delivered precisely where it is needed, whether this is a return of the cholesterol to the liver or an uptake of cholesterol by cells in extrahepatic tissues. CE Cell in peripheral tissue

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues LDL FFA TG LDL receptor TG Adipose tissue CE Liver New synthesis also contributes to cellular cholesterol. LDL receptor CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LPL: lipoprotein lipase TG: triglycerides CE New synthesis FC Cell in peripheral tissue

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues LDL FFA TG LDL receptor TG Adipose tissue CE Liver Only the liver and those endocrine tissues that synthesise steroid hormones have the ability to metabolise the cholesterol molecule. Other tissues are totally dependent on an efflux to acceptors in the extracellular space to remove their surplus cholesterol. The predominant extracellular acceptors are HDLs. There are at least three distinct processes (mediated by activities of ABCA1, ABG1 and SR-B1) that promote the efflux of cholesterol from cells. Lecithin:cholesterol acyltransferase (LCAT) esterifies cholesterol on the surface of HDL particles in a process that moves the cholesterol into the inside of the particle. LDL receptor CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE CE Adipose and other tissues LDL FFA TG LDL receptor TG Adipose tissue CE Liver CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides Once the cholesterol has been transferred from cells to HDLs in the extracellular space, it may be delivered to the liver in a process involving binding of HDLs to SR-B1. LDL receptor CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE CE Adipose and other tissues LDL FFA TG LDL receptor TG Adipose tissue CE Liver CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides The cholesterol taken up by the liver may be recycled into VLDL. LDL receptor CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE CE Adipose and other tissues LDL FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver LDL receptor CE: cholesteryl ester FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides The cholesterol taken up by the liver may also be released into bile, either as unchanged cholesterol or after being converted into bile acids. CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Plasma Lipid Transport Liver VLDL LPL FFA TG FC CE TG CE CE Adipose and other tissues LDL FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver In some species, including humans, non-human primates and rabbits, the cholesterol in HDL may also be delivered to the liver by an indirect pathway involving the cholesteryl ester transfer protein-mediated transfer of HDL cholesteryl esters to the VLDL/LDL fractions, with delivery to the liver then being achieved by the receptor-mediated uptake of LDL. LDL receptor CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides CETP CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues CE LDL FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver LDL receptor CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides CETP CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver VLDL LPL FFA TG FC CE TG CE Adipose and other tissues CE LDL  FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides In diabetes and the metabolic syndrome there is an increase in release of free fatty acids (FFA) from adipose tissue. A proportion of this is taken up by the liver and converted into triglyceride. LDL receptor CETP CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver  VLDL LPL FFA TG FC CE TG CE Adipose and other tissues CE LDL  FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides This leads to an increased synthesis and secretion of VLDL and an increase in concentration of VLDL triglyceride in plasma. LDL receptor CETP CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver  VLDL  LPL FFA TG FC CE TG Adipose and other tissues CE CE LDL  FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver LDL receptor CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides There is also a decreased activity of lipoprotein lipase resulting in a decreased rate of breakdown of triglyceride and a further increase in the concentration of triglyceride in plasma. CETP CE TG TG New synthesis LCAT CE FC Cell in peripheral tissue HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver  VLDL  LPL FFA TG FC CE TG Adipose and other tissues CE CE LDL  FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver LDL receptor CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides A decrease in delivery of cell cholesterol to HDL has the capacity to decrease the concentration of HDL cholesterol. CETP CE TG TG New synthesis  LCAT CE FC Cell in peripheral tissue  HDL

Dyslipidemia in Diabetes and the Metabolic Syndrome Liver  VLDL  LPL FFA TG FC CE TG Adipose and other tissues CE CE LDL  FFA FC TG LDL receptor TG Adipose tissue CE Bile Liver CE: cholesteryl ester CETP: cholesteryl ester transfer protein FC: free cholesterol FFA: free fatty acids LCAT: lecithin cholesterol acytransferase LPL: lipoprotein lipase TG: triglycerides An increase in the cholesteryl ester transfer protein-mediated transfer of cholesterol from HDL to the expanded VLDL pool further reduces the concentration of HDL cholesterol. LDL receptor CETP CE TG TG New synthesis  LCAT CE FC Cell in peripheral tissue  HDL

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