Outline

18.1 Phospholipids and Sphingolipids: Synthesis and Intracellular Movement

18.2 Cholesterol: A Multifunctional Membrane Lipid

18.3 Lipid Movement into and out of Cells

18.4 Feedback Regulation of Cellular Lipid Metabolism

18.5 The Cell Biology of Atherosclerosis, Heart Attacks, and Strokes

Water-soluble lipid precursors bV^^n^^^ /membrane

Interorganelle lipid transport

Water-soluble lipid precursors

Interorganelle lipid transport

Extracellular OR Lipoproteins binding protein

Atherosclerosis, heart attack, stroke

Receptor-mediated selective uptake

Extracellular OR Lipoproteins binding protein

Atherosclerosis, heart attack, stroke

Receptor-mediated selective uptake

▲ FIGURE 18-1 Overview of synthesis of major membrane lipids and their movement into and out of cells. Membrane lipids (e.g., phospholipids, cholesterol) are synthesized through complex multienzyme pathways that begin with sets of water-soluble enzymes and intermediates in the cytosol (1) that are then converted by membrane-associated enzymes into water-insoluble products embedded in the membrane (2), usually at the interface between the cytosolic leaflet of the endoplasmic reticulum (ER) and the cytosol. Membrane lipids can move from the ER to other organelles ( 3), such as the Golgi apparatus or the mitochondrion, by either vesicle-mediated or other poorly defined mechanisms. Lipids can move into or out of cells by plasma-membrane transport proteins or by lipoproteins. Transport proteins similar to those described in Chapter 7 that move lipids (4) include sodium-coupled symporters that mediate import; CD36 and SR-BI superfamily proteins that can mediate stroke), the number one cause of death in Western industrialized societies. We describe current theories about why large arteries can become clogged with cholesterol-containing deposits and how cells recognize the differences between unidirectional or bidirectional transport; and ABC superfamily proteins that mediate cellular export, the flipping of lipids from the cytosolic to the exoplasmic leaflet of the membrane, or both. Because lipids are insoluble in water, the transport proteins move lipids from and to carrier proteins, lipoproteins, membranes, or other lipid-binding complexes in the extracellular space and the cytosol. Lipoproteins assembled in the ER carry in their hydrophobic cores large amounts of lipid. They are secreted by the classic Golgi-mediated secretory pathway ( 5), and their lipids are imported either through (6) receptor-mediated endocytosis or through ( 7|) receptor-mediated selective lipid uptake. Cellular lipid metabolism is regulated (8) by nuclear receptor transcription factors that directly bind lipids and by nuclear sterol regulatory element-binding proteins (nSREBPs) that are generated by proteolysis of an integral membrane protein precursor in the Golgi.

"good" and "bad" cholesterol. As you will see, detailed knowledge of the fundamental cell biology of lipid metabolism has led to the discovery of remarkably effective anti-atherosclerotic drugs.

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