A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids
Alimentary Pharmacology & Therapeutics, vol. 58, pp. 238–249
Abstract
BACKGROUND: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis. AIM: To examine the effects of missense variants in MTTP on hepatic and circulating lipids. METHODS: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444). RESULTS: We analysed 24 missense variants in MTTP in PMBB for association with biopsy-proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873-A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging-proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL-cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele. CONCLUSIONS: MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure-function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.
Authors 17
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Universitätsklinikum Aachen · University of Pennsylvania · RWTH Aachen University
Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Medicine, Division of Translational Medicine and Human Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Medicine, Division of Translational Medicine and Human Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine, Division of Gastroenterology and Hepatology Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Foundations of Medicine NYU Long Island School of Medicine Mineola New York USA
Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, New York, USA
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Universitätsklinikum Aachen · University of Pennsylvania · RWTH Aachen University
Affiliation as printed
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Aachen Germany
Department of Microbiology Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Affiliation as printed
Department of Foundations of Medicine NYU Long Island School of Medicine Mineola New York USA
Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, New York, USA
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Affiliation as printed
Department of Medicine, Division of Translational Medicine and Human Genetics Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania USA
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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