JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Reduces Food Preference for Fat

Abstract

Microsomal triglyceride transfer protein (MTP) is involved in the assembly and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. JTT-130 is a novel intestine-specific MTP inhibitor, which has been shown to be useful in the prevention and treatment of dyslipidemia, obesity, and diabetes. JTT-130 has also been shown to suppress food intake in a dietary fat-dependent manner in rats. However, whether JTT-130 enables changes in food preference and nutrient consumption remains to be determined. Therefore, the aim of the present study was to investigate the effects of JTT-130 on food preference in rat under free access to two different diets containing 3.3% fat (low-fat diet, LF diet) and 35% fat (high-fat diet, HF diet). JTT-130 decreased HF diet intake and increased LF diet intake, resulting in a change in ratio of caloric intake from LF and HF diets to total caloric intake. In addition, macronutrient analysis revealed that JTT-130 did not affect carbohydrate consumption but significantly decreased fat consumption (P < 0.01). These findings suggest that JTT-130 not only inhibits fat absorption, but also suppresses food intake and specifically reduces food preference for fat. Therefore, JTT-130 is expected to provide a new option for the prevention and treatment of obesity and obesity-related metabolic disorders.

Fish Oil Supplementation Alleviates the Altered Lipid Homeostasis in Blood, Liver, and Adipose Tissues in High-Fat Diet-Fed Rats

“…It meant that the improvement of imbalance of plasma lipid or cholesterol could be through reducing expressions or activities of both intestinal MTTP and ABCA1. Moreover, JTT-130 has been discovered to act as a intestine-specific MTTP inhibitor and ameliorate lipid metabolism and hyperglycemia in HFD-fed rats and Zucker diabetic fatty rats. − In the present study, HFD feeding may contribute to downregulation and upregulation of MTTP protein expression in the liver and the intestine, respectively, while supplementation of 5% FO could reverse this adverse effect, leading to reducing accumulation of hepatic TG and TC and enforcing excretion of fecal TG and TC. However, the detailed mechanism between FO and ABCA1 in the lipid metabolism remains for further investigation.…”

Acyl-CoA:diacylglycerol acyltransferase 1 inhibition in the small intestine increases plasma transaminase activity via the activation of protein kinase C pathway

“…JTT-130 used as an intestinal MTP inhibitor was designed to be rapidly hydrolyzed to an inactive metabolite after absorption from the small intestine and to inhibit intestinal MTP specifically. This MTP inhibitor was reported to suppress an increase in 14 C radioactivity in blood as well as in the upper small intestine and the luminal content after [ 14 C]triolein loading (Mera et al, 2011). It was thus expected that TAG was retained in the enterocytes after corn oil loading in rats pretreated with the MTP inhibitor.…”

“…JTT-553, which is a selective DGAT1 inhibitor (Tomimoto, et al, 2015a(Tomimoto, et al, , 2015b, JTP-103237, 7-(4,6- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine derivative, which is a selective MGAT2 inhibitor (Okuma, et al, 2015), and amino]phenyl} acetyloxymethyl)-2-phenylmalonate, which is a selective intestinal MTP inhibitor (Mera, et al, 2011), were synthesized in the Central Pharmaceutical Research Institute, Japan Tobacco Inc. (Osaka, Japan).…”

“…Separately, the intestinal MTP inhibitor, JTT-130 (10 mg/kg) dissolved in vehicle [polyethylene glycol 400 (PEG400; Toho Yakuhin Co., Ltd., Tokyo, Japan)] or the vehicle alone was administered orally to rats (five animals per group) at 2.0 mL/kg after overnight fasting. The dose level of JTT-130 was determined according to the previous report on its pharmacological study (Mera, et al, 2011). At 0.5 hr after the dosing, corn oil (1 g/kg) or DW was administered orally to the animals at 1.1 mL/ kg.…”

“…In this study, we have further investigated the mechanism for the JTT-553-induced increase in blood transaminase activity. Especially, we sought to identify a lipid component responsible for the elevation using inhibitors for monoacylglycerol acyltransferase 2 (MGAT2) (Okuma et al, 2015) and intestinal microsomal triglyceride transfer protein (MTP) (Mera et al, 2011) as well as JTT-553 and fatty acids (FAs).…”