1;Signaling Pathways in Liver Diseases;1 1.1;The Cell Types and the Matrix;13 1.1.1;Hepatocytes;14 1.1.1.1;Introduction;14 1.1.1.2;Hepatocyte Development;14 1.1.1.3;Hepatocyte Structure and Renewal;16 1.1.1.4;Plasmamembrane;17 1.1.1.4.1;The Basolateral or Sinusoidal Domain;17 1.1.1.4.2;The Canalicular or Apical Domain;17 1.1.1.4.3;The Lateral Domain;18 1.1.1.4.4;Tight Junctions, Gap Junctions, and Desmosomes;18 1.1.1.5;Organelles;18 1.1.1.5.1;Endoplasmic Reticulum;18 1.1.1.5.2;Golgi Complex;19 1.1.1.5.3;Mitochondria;19 1.1.1.5.4;Lysosomes;20 1.1.1.5.5;Peroxysomes;20 1.1.1.6;Nucleus/Polyploidy;20 1.1.1.7;Physiology;21 1.1.1.7.1;Lipid/Lipoprotein, Cholesterol, and Bile Metabolism;21 1.1.1.7.2;Glucose Metabolism;22 1.1.1.7.3;Amino Acid and Ammonia Metabolism;25 1.1.1.7.4;Protein Synthesis;25 1.1.1.7.5;Acute Phase Response;25 1.1.1.7.6;Iron Metabolism;26 1.1.1.7.7;Hepatocyte as an Endocrine Cell;26 1.1.1.7.8;Transport-Systems;27 1.1.1.7.8.1;Na+ Dependent Bile Salt Uptake;27 1.1.1.7.8.2;Na+ Independent Hepatic Uptake of Amphipatic Substrates: The Organic Anion Transporting Polypeptide Family (OATP);27 1.1.1.7.8.3;Na+ Independent Hepatic Uptake of Hydrophilic Organic Cations and Anions: The Organic Ion Transporter Family (OAT/OCT);28 1.1.1.7.8.4;Basolateral Efflux Pumps;29 1.1.1.7.8.5;Bile Salt Excretion;29 1.1.1.7.8.6;Excretion of Nonbile Salt Organic Anions;29 1.1.1.7.8.7;Phospholipid Excretion;29 1.1.1.7.8.8;Copper Excretion;30 1.1.1.8;Summary;30 1.1.2;References;32 1.1.3;Signaling Pathways in Biliary Epithelial Cells;36 1.1.3.1;Introduction;36 1.1.3.2;Membrane Receptors;36 1.1.3.3;Cyclic Adenosine 3', 5'-Monophosphate (cAMP);38 1.1.3.4;Cytosolic Ca2+;39 1.1.3.5;Protein Kinase C;42 1.1.3.6;MAPK Signaling;42 1.1.3.7;PI3-Kinase Signaling;43 1.1.3.8;Pathological Conditions;44 1.1.3.9;Summary;45 1.1.4;References;45 1.1.5;Stellate Cells;51 1.1.5.1;Polypeptide Growth Factor Receptors;54 1.1.5.2;TGF-b Receptor Superfamily;57 1.1.5.3;Seven Transmembrane Domain Receptors;59 1.1.5.4;TNF Receptor Superfamily;61 1.1.5.5;Nuclear Receptor Family;63 1.1.5.6;Other Cytokine Receptors;64 1.1.5.7;Adipokine Receptors;65 1.1.5.8;Cooperation Between Growth Factor Receptor and Integrin Signaling;66 1.1.5.9;HSC and Toll-like Receptors (TLRs);67 1.1.5.10;Cannabinoids Receptors;68 1.1.5.11;Hedgehog Signal Pathway (See Also Chapter on this Pathway);68 1.1.5.12;Senescence of Activated Stellate Cells;69 1.1.5.13;Summary;69 1.1.6;References;70 1.1.7;Signaling Pathways in Liver Diseases Kupffer Cells;79 1.1.7.1;Introduction;79 1.1.7.2;Molecular Mechanisms of Kupffer Cell Activation;79 1.1.7.3;Kupffer Cell: Neutrophil Interaction in Host Defense, Immune Tolerance, and Liver Regeneration;81 1.1.7.3.1;Host Defense;81 1.1.7.3.2;Immune Tolerance;81 1.1.7.3.3;Liver Regeneration;82 1.1.7.4;Role of Kupffer Cells in Liver Injury;83 1.1.7.4.1;Acetaminophen;83 1.1.7.4.2;Ischemia-Reperfusion Injury;83 1.1.7.4.3;Alcoholic Liver Disease;84 1.1.7.5;Kupffer Cells and Portal Pressure;84 1.1.7.6;Summary;85 1.1.8;References;85 1.1.9;Hepatic Sinusoidal Endothelial Cells;89 1.1.9.1;Development and Structure;89 1.1.9.2;Cellular Functions;89 1.1.9.2.1;Fenestration/Filtration;89 1.1.9.2.2;Expression of Adhesion Molecules;90 1.1.9.2.3;Signaling;91 1.1.9.2.4;Metabolism;92 1.1.9.2.5;Role in Blood Clearance;92 1.1.9.2.6;Antigen Presentation;92 1.1.9.3;Pathobiology;93 1.1.9.3.1;Alcoholic Liver Disease;93 1.1.9.3.2;Nonalcoholic Fatty Liver Disease;93 1.1.9.3.3;Portal Hypertension/Cirrhosis;93 1.1.9.3.4;Angiogenesis/Hepatic Malignancies;95 1.1.9.3.5;Drug Toxicity;95 1.1.9.3.6;Cellular Rejection;96 1.1.9.3.7;Ischemia-Reperfusion Injury;96 1.1.9.3.8;Aging Process;97 1.1.9.4;Summary;97 1.1.10;References;98 1.1.11;Extracellular Matrix;102 1.1.11.1;Introduction;102 1.1.11.2;Components of the ECM in Liver;102 1.1.11.2.1;The Collagen Scaffold;103 1.1.11.2.2;Proteoglycans;104 1.1.11.2.3;Laminin;104 1.1.11.2.4;Fibronectin;104 1.1.11.2.5;Matricellular Proteins;106 1.1.11.3;Changes in ECM from Normal