Identification of novel factors in enterocytes involved in dietary fat absorption and energy balance
Abstract
Obesity and obesity-related diseases are multifactorial diseases in which tissue to tissue communication is impaired. However, the role of metabolism within the intestine in these diseases has been largely ignored. Chylomicron secretion from the intestine is thought to depend primarily on the amount of dietary fat consumed because of its high efficiency. However, recent studies indicate that regulation of chylomicron secretion from the intestine affects postprandial triglyceride (TG) levels in the blood and even whole body energy balance. The purpose of these studies is to reveal the underappreciated roles of the intestine in TG and whole body energy metabolism during dietary fat absorption (DFA). Diaclyglycerol acyltrasferase (DGAT)-1 catalyzes the final, committed step of TG synthesis. DGAT1-/- mice are resistant to diet-induced obesity due in part to increased energy expenditure. DGAT1-deficient mice have abnormal TG storage in and delayed secretion of chylomicron from the intestine during DFA. However, the role of the intestine phenotype in the resistance to diet-induced obesity phenotype of DGAT1-/- mice is unknown. Therefore, in the first study, we examined whether the restoration of DGAT1 only in the intestine reverses the resistance of diet-induced obesity pheynotype in DGAT1-/- mice. We found that Dgat1IntONLY and DGAT1-/- mice completely lack or have abundant TG storage in CLDs in enterocytes, respectively. Despite lacking DGAT1 in liver and adipose tissue, we found that Dgat1IntONLY mice are not resistant to high-fat (HF) diet-induced hepatic steatosis or obesity, indicating that intestine specific DGAT1 expression in mice stimulates dietary TG secretion out of the enterocytes and thereby contributing to weight gain after HF diet feeding and is enough to reverse the phenotypes of DGAT1 -/- mice. Various studies imply that intestine may have a temporal TG storage during DFA, but it has been unclear. Therefore, in the second study, we examined the ability of the intestine to store TGs during DFA and found that enterocytes dynamically store TGs in cytoplasmic lipid droplets (CLDs). A dynamic pool of TG storage in enterocytes expands and depletes relative to time post dietary fat challenge. To identify cellular factors which may play a role in the regulation of the dynamic CLD storage, we investigated the expression and localization of PAT proteins, which are known to be related to CLD metabolism in various cell types, in enterocytes of mice chronically and acutely challenged by dietary fat. We found that adipophilin and Tip47 are the only PAT genes present in mouse intestinal mucosa and both genes are present at higher levels after HF challenges. In addition, TIP47, but not adipophilin, coats CLDs in enterocytes after an acute HF challenge suggesting that TIP47 plays a role in the synthesis of CLDs from newly synthesized TG at the beginning of the process of DFA in enterocytes. Adipophilin, on the other hand, coats CLDs only in enterocytes of chronic HF fed mice suggesting that adipophilin may play a role in the stabilization of TG stored in CLDs in longer term. These results suggest distinct roles for TIP47 and adipophilin in DFA. Taken together, these results highlight novel roles of the intestine during DFA. The intestine has a temporal storage of TGs as CLDs during dynamic process of DFA and the CLD metabolism may be in part regulated by TIP47 and adipophilin differently depending on the state of CLD maturation. In addition, the balance between CLD storage and TG secretion rate in and from the intestine play an important role in regulating whole body energy balance.
Degree
Ph.D.
Advisors
Buhman, Purdue University.
Subject Area
Cellular biology|Physiology
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