LDL Receptor-Mediated Endocytosis

Receptor-Mediated Endocytosis of LDL

• LDL was conjugated with ferritin to permit electron microscopic visualization, allowing the study of its uptake by a scavenger receptor.
• The LDL-ferritin complex binds to a coated pit on the surface of a cultured human fibroblast, which then forms an endocytotic vesicle.
• Clathrin, the major protein in coated pits, forms triskelions that assemble into polyhedral lattices, composing a cage-like structure.

Involvement of LDL Receptors in Cholesterol Uptake and Metabolism

• LDL receptors play a crucial role in cholesterol uptake and metabolism.
• Polyunsaturated fat (PUFA) ingestion is correlated with low plasma cholesterol levels, although the mechanisms involved are not fully understood.

Mobilization of Adipose Cell Triacylglycerols by Lipolysis

• Lipolysis is the process of hydrolyzing triacylglycerols (TG) to glycerol and free fatty acids (FFA) in adipose cells.
• Three lipases act sequentially to hydrolyze TG: lipase, hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL).
• Exported FFA is bound to albumin for transport to liver and other tissues for oxidation.
• Glycerol is released to the blood and taken up by liver cells, where it serves as a gluconeogenic substrate.

Control of Lipolysis in Adipose Cells

• Lipolysis is controlled by a cAMP-mediated cascade system, involving hormonal activation of a β-adrenergic G-protein coupled receptor.
• cAMP activates protein kinase A (PKA), which phosphorylates perilipin (PL) and HSL, leading to the recruitment of ATGL and the hydrolysis of TG.

Fatty Acid Oxidation

• Knoop's experiments demonstrated the β-oxidation of fatty acids, showing that even-numbered carbon chains result in phenylacetic acid, while odd-numbered chains result in benzoic acid.

Biosynthesis of Ketone Bodies

• When carbohydrate catabolism is limited, acetyl-CoA is converted to ketone bodies, mainly acetoacetate and β-hydroxybutyrate, in the liver.

Fatty Acid Biosynthesis

• Acetyl-CoA is the key intermediate between fat and carbohydrate metabolism, and citrate serves as a carrier to transport acetyl units from the mitochondrion to the cytosol for fatty acid synthesis.
• The synthesis of malonyl-CoA from acetyl-CoA and bicarbonate is the first committed step in fatty acid biosynthesis.
• Malonyl-CoA represents an activated source of two-carbon fragments for fatty acid biosynthesis, with the loss of CO2 driving C-C bond formation.

Chemical Similarities between Oxidation and Synthesis of a Fatty Acid

• The chemical similarities between fatty acid oxidation and synthesis are due to the involvement of similar intermediates and electron carriers.

Structure and Swinging Arm Mechanism in the Mammalian Fatty Acid Synthase Complex

• The fatty acid synthase complex is an organized multienzyme complex that contains multifunctional proteins.
• The complex includes a swinging arm mechanism, where the activated acyl group is transferred between different active sites.

Steroid Metabolism

• The five carbons of isoprene could be derived metabolically from three molecules of acetate.
• Cholesterol biosynthesis can be considered as three distinct processes: conversion of C2 fragments to a C6 isoprenoid precursor, conversion of six C6 mevalonates to the C30 squalene, and cyclization of squalene to the C27 cholesterol.
• The biosynthesis of mevalonate and its conversion to isopentenyl pyrophosphate and dimethylallyl pyrophosphate involve a series of phosphorylations and decarboxylations.
• The conversion of farnesyl pyrophosphate to squalene is catalyzed by squalene synthase, involving a cyclopropane intermediate and hydride transfer from NADPH.

Regulation of HMG-CoA Reductase

• HMG-CoA reductase is regulated by ubiquitin-mediated proteolysis, where sterol binding leads to rapid degradation of the enzyme.
• Statins, such as lovastatin and simvastatin, are specific inhibitors of HMG-CoA reductase, acting by competitive inhibition.