This report describes a model of obesity and cardiomyocyte regulation of systemic lipid levels using the Drosophila gene Mtp. Dmel\Mtp is orthologous to the human gene MTTP (microsomal triglyceride transfer protein), which plays a key role in lipoprotein assembly. MTTP has been associated with HDL cholesterol level in a GWAS study; there is also evidence that a common MTTP variant is protective against impaired glucose tolerance, type II diabetes, and other parameters of the metabolic syndrome. Loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\Mtp.
The human MTTP gene has not been introduced into flies.
Dmel\Mtp was identified in a genetic screen for genes that could alter the pathogenesis of high-fat diet (HFD)-induced obesity in Drosophila (see FBhh0000495). Newly eclosed adults were assayed for whole-body triglyceride (TG) levels after being exposed as larvae to a high-fat diet (HFD) or a normal fat-diet (NFD). Systemic knockdown of Mtp, effected by RNAi, causes resistance to HFD-induced gain in triglyceride levels seen in wild-type flies. Knockdown of Mtp specifically in the fat body results in a modest reduction in whole-body triglyceride levels on a normal fat-diet (NFD), however, it does not ameliorate the increase in triglyceride levels precipitated by a HFD.
This system has been used to assess cardiomyocyte-specific regulation of triglyceride levels. Knockdown of Mtp specifically in cardiomyocytes results in a significant reduction in whole-body triglyceride levels on a NFD. In addition (and in contrast to fat-body), cardiomyocyte-specific reduction of Mtp expression leads to a dramatic decrease in whole-body TG levels on a HFD, relative to that observed for control animals. A small number of physical interactions have been described for Dmel\Mtp; see below and in the Mtp gene report.
These results add to growing evidence that cardiomyocytes play an important role in the regulation of systemic lipid homeostasis; see also human disease models 'obesity and cardiomyocyte regulation of systemic lipid levels, APOB-related' (FBhh0001198); 'obesity and cardiomyocyte regulation of systemic lipid levels, SNAIL TF genes-related' (FBhh0001199); 'obesity, susceptibility to (postulated), MED13-related' (FBhh0000506); 'obesity, susceptibility to (postulated), MED12-related' (FBhh0000507).
[updated Feb. 2020 by FlyBase; FBrf0222196]
Obesity is an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. Obesity is associated with increased risk of illness, disability, and death. (http://medical-dictionary.thefreedictionary.com/obesity).
The development of obesity is recognized as having both genetic and environmental components (https://www.sciencelearn.org.nz/resources/203-obesity-genetic-or-environmental).
There is growing evidence that cardiomyocytes play an important role in the regulation of systemic lipid homeostasis (FBrf0234631, FBrf0244152, and references cited therein).
The adult mammalian heart has the ability to switch energy sources as dictated by substrate availability, hormonal status, and physiological conditions. Sixty to 90% of the energy used by the adult fasting heart is provided by the mitochondrial oxidation of long-chain fatty acids (FAs), with the remainder supplied by oxidation of glucose, lactate and ketone bodies. (Pascual and Coleman, 2016; pubmed:26993579)
MTTP is associated with HDL cholesterol level in a GWAS study (see GWAS Catalog, below in 'External links').
A common variant of MTTP, I128T, may be protective against impaired glucose tolerance, type II diabetes, and other parameters of the metabolic syndrome (Rubin, et al., 2006; pubmed:16721486). [from MIM:605552, MIM:157147; 2020.02.21] See also ClinVar, 14242.
MTTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein and plays a central role in lipoprotein assembly. [Gene Cards, MTTP; 2020.02.24]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human MTTP (1 Drosophila to 1 human). Dmel\Mtp shares 25% identity and 45% similarity with the human gene.
