title: Contemporary aspects of the biology and therapeutic regulation of the microsomal triglyceride transfer protein.
abstract: The microsomal triglyceride transfer protein (MTP), the product of the MTTP gene, is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins, but when defective causes abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the inability to produce chylomicrons or very low-density lipoproteins, with the absence of apolipoprotein B-containing lipoproteins in the circulation. Knowledge of the molecular basis for abetalipoproteinemia has led to the development of therapies for dyslipidemia that inhibit MTP. Partial MTP inhibition using small molecule inhibitors, such as lomitapide, can effectively lower plasma low-density lipoprotein-cholesterol and apolipoprotein B levels, but is associated with gastrointestinal side effects and hepatic steatosis, whose long-term sequelae remain unclear; lomitapide has accordingly only been approved as a treatment for homozygous familial hypercholesterolemia. Intestine-specific inhibitors of MTP decrease chylomicron biogenesis and improve insulin sensitivity in experimental animals and, while overcoming hepatic steatosis, may have significant gastrointestinal side effects that could limit their use in humans. We review contemporary aspects of the biology and therapeutic regulation of MTP and their significance for lipid metabolism and cardiovascular disease.
authors.affiliation: Department of Clinical Biochemistry, PathWest Laboratory Medicine WA (A.J.H., J.R.B.), School of Medicine and Pharmacology (A.J.H., J.R.B., G.F.W.), School of Pathology and Laboratory Medicine (A.J.H), and Lipid Disorders Clinic, Cardiovascular Medicine (J.R.B., G.F.W), Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hooper
authors.affiliation: Department of Clinical Biochemistry, PathWest Laboratory Medicine WA (A.J.H., J.R.B.), School of Medicine and Pharmacology (A.J.H., J.R.B., G.F.W.), School of Pathology and Laboratory Medicine (A.J.H), and Lipid Disorders Clinic, Cardiovascular Medicine (J.R.B., G.F.W), Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.affiliation: Department of Clinical Biochemistry, PathWest Laboratory Medicine WA (A.J.H., J.R.B.), School of Medicine and Pharmacology (A.J.H., J.R.B., G.F.W.), School of Pathology and Laboratory Medicine (A.J.H), and Lipid Disorders Clinic, Cardiovascular Medicine (J.R.B., G.F.W), Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia. gerald.watts@uwa.edu.au.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
mesh_terms: D000012:Abetalipoproteinemia / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D017433:Protein Structure, Secondary
chemical_list: C473731:BMS201038; D001562:Benzimidazoles; D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein
keywords: LDL-cholesterol; abetalipoproteinemia; familial hypercholesterolemia; lomitapide; microsomal triglyceride transfer protein