New approaches to target microsomal triglyceride transfer protein
Mohammed Mahmood Hussain1, Ahmed Bakillah
1Departments of Anatomy and Cell Biology, and Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. mhussain@downstate.edu
Current Opinion in Lipidology
|October 30, 2008
Summary
New strategies targeting microsomal triglyceride transfer protein (MTP) aim to reduce plasma lipids and inflammation. Researchers propose novel approaches to mitigate side effects like elevated liver enzymes associated with MTP inhibition.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Microsomal triglyceride transfer protein (MTP) is crucial for synthesizing lipoproteins and CD1d.
- MTP is a therapeutic target for lowering plasma lipids and inflammation.
- Current MTP inhibition strategies can cause adverse effects, including increased transaminases and tissue lipids.
Purpose of the Study:
- To explore novel therapeutic strategies for MTP inhibition.
- To identify methods for avoiding side effects associated with MTP inhibition.
- To investigate alternative MTP targeting approaches for lipid and inflammation management.
Main Methods:
- Identification of inositol requiring enzyme 1beta as an intestine-specific MTP regulator.
- Investigation of MTP's role in cholesterol ester biosynthesis.
- Analysis of MTP's phospholipid transfer activity in lipoprotein lipidation.
- Observation of diurnal variations and food-induced changes in MTP expression.
Main Results:
- Inositol requiring enzyme 1beta regulates MTP in the intestine.
- MTP plays a role in cholesterol ester biosynthesis.
- Phospholipid transfer activity is key for MTP's role in lipidation.
- MTP expression exhibits diurnal variation and is influenced by food intake.
Conclusions:
- Proposed strategies include upregulating inositol requiring enzyme 1beta, reducing cellular lipids, and targeting MTP activity or protein interactions.
- Specific inhibition of MTP's phospholipid or triglyceride transfer activities may offer benefits.
- Short-lived MTP antagonists could be effective for managing lipids and preventing steatosis.
- Addressing the link between MTP inhibition and liver enzyme elevation is critical for viable MTP-targeted therapies.
Related Concept Videos
01:29Pharmacogenomics: Identification of New Drug Targets
Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion, mediated...
A recent model describes pravastatin's hepatobiliary excretion, mediated...