Date Published: August 9, 2017
Publisher: Public Library of Science
Author(s): Larry L. Swift, Joseph D. Love, Carla M. Harris, Benny H. Chang, W. Gray Jerome, Clarissa Menezes Maya-Monteiro.
Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice. MTP expression was reduced approximately 55% in white fat and 65–80% in brown fat. Reducing MTP expression in adipose tissue had no effect on weight gain or body composition, whether the mice were fed a regular rodent or high fat diet. In addition, serum lipids and unesterified fatty acid levels were not altered in the knockdown mice. Importantly, decreased MTP expression in adipose tissue was associated with smaller lipid droplets in brown fat and smaller adipocytes in white fat. These results combined with our previous studies showing MTP lipid transfer activity is not necessary for lipid droplet initiation or growth in the early stages of differentiation, suggest that a structural feature of the MTP protein is important in lipid droplet maturation. We conclude that MTP protein plays a critical role in lipid droplet maturation, but does not regulate total body fat accumulation.
Our laboratory was the first to report the presence of microsomal triglyceride transfer protein (MTP) in adipocytes of mice, rats, and humans . Immunohistochemical studies revealed MTP surrounding lipid droplets in both brown and white fat. Immunofluorescence studies suggested that MTP was associated with the surface of the lipid droplet , an observation that was confirmed by confocal and electron microscopic studies . In addition, we showed that MTP was expressed in mouse 3T3-L1 cells  and that protein levels increased nearly five-fold as the cells differentiated into adipocytes . Furthermore, as the cells differentiated, MTP moved from the juxtanuclear region of the cell to the surface of the droplet . Taken together, our observations suggested that MTP is involved in lipid droplet biology. In particular, we hypothesized that MTP was involved in the formation and/or maturation of lipid droplets. However, our studies with 3T3-L1 cells have shown that inhibition of MTP activity has no effect on the differentiation of these cells into adipocytes as assessed by the percent of cells that contain lipid droplets or the number of lipid droplets per cell . In addition, inhibition of MTP activity had no effect on the movement of triglyceride out of fully differentiated 3T3-L1 cells either as a lipid complex or via lipolysis . While these are important observations, they provide only limited insight into the primary function of MTP within the adipocyte.
MTP has long been known to be essential for the assembly of triglyceride-rich apolipoprotein (apo) B-containing lipoproteins by hepatocytes and enterocytes , presumably transporting neutral lipid from the membrane of the endoplasmic reticulum(ER) to nascent lipoproteins forming in the lumen of the ER. Once thought to be only present in the liver and intestine, studies have shown that MTP is expressed in a wide range of tissues, including myocardium [11–13], retina , kidney [15, 16], yolk sac [17, 18], and placenta . MTP is also expressed in ovary and testis , as well as fat , tissues that do not express apoB nor do they secrete lipoprotein particles. Within these tissues MTP may serve specialized needs in lipid trafficking and/or storage beyond the classical role of triglyceride transport.