Growth Hormone and Pparα in the Regulation of Genes Involved in Hepatic Lipid Metabolism

............................................................... 4 LIST OF PUBLICATIONS............................................. 5 ABBREVIATIONS....................................................... 6 TABLE OF CONTENTS................................................. 8 INTRODUCTION........................................................ 10 GENERAL INTRODUCTION............................................................. 10 LIPOPROTEIN METABOLISM.......................................................... 10 Lipoproteins.................................................................................... 10 Exogenous lipoprotein pathway.......................................................... 11 Endogenous lipoprotein pathway........................................................ 12 Atherogenic dyslipidemia.................................................................. 13 APOB AND VLDL.............................................................................. 14 ApoB............................................................................................. 14 VLDL assembly............................................................................... 15 MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN.................. 16 Regulation of MTP........................................................................... 17 STEROL REGULATORY ELEMENT BINDING PROTEINS............... 17 The two-step cleavage process of SREBPs............................................ 18 SREBP-1c and regulation of lipogenesis.............................................. 19 LIPOGENIC ENZYMES..................................................................... 19 Acetyl-CoA carboxylase.................................................................... 19 Fatty acid synthase........................................................................... 20 Stearoyl-CoA desaturase................................................................... 20 Glycerol-3-phosphate acyltransferase.................................................. 21 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS............ 21 PPARα and lipid metabolism............................................................. 22 GROWTH HORMONE....................................................................... 22 The GH secretory pattern in females and males..................................... 23 GH receptor and GH signalling.......................................................... 24 Influence of the GH secretory pattern on GH signalling.......................... 25 Insulin-like and diabetogenic effects of GH.......................................... 25 GH and lipoprotein metabolism in humans........................................... 26 GH and lipoprotein metabolism in laboratory animals........................... 26 Growth hormone and PPARα in the regulation of genes involved in hepatic lipid metabolism 9 AIMS OF THE THESIS................................................ 28 METHODOLOGICAL CONSIDERATIONS ..................... 29 ANIMALS.......................................................................................... 29 Hypophysectomised rats.................................................................... 29 HORMONAL TREATMENT.............................................................. 29 Thyroxine (T4)................................................................................. 29 Glucocorticoids............................................................................... 29 Growth hormone.............................................................................. 30 Insulin........................................................................................... 31 Sex steroids.................................................................................... 31 HEPATOCYTE CULTURES............................................................... 32 SUMMARY OF RESULTS............................................. 34 PAPER I............................................................................................ 34 PAPER II........................................................................................... 35 PAPER III.......................................................................................... 36 PAPER IV.......................................................................................... 37 GENERAL DISCUSSION................................................. 39 REGULATION OF LIPOGENESIS AND VLDL SECRETION BY GH............................................................................................... 39 REGULATION OF LIPOGENESIS AND VLDL SECRETION BY INSULIN...................................................................................... 41 REGULATION OF SREBP-1c AND LIPOGENIC ENZYMES............... 43 REGULATION OF MTP POSSIBLE MECHANISMS OF GH ACTION.................................................................................44 IMPORTANCE OF CHANGED MTP LEVELS FOR THE EFFECTS OF PPARα......................................................................... 46 MTP AND DIFFERENT REGULATION OF APOB-48 AND APOB-100.................................................................................. 47 SUMMARY AND CONCLUSIONS................................. 49 ACKNOWLEDGEMENTS....................................... ...... 51 REFERENCES............................................................ 54