Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Sachdev, V.
Deciphering the role of intestinal DGAT1 in lipid
and energy homeostasis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 139
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
- Steyrer Ernst
- Altmetrics:
- Abstract:
- Obesity and its associated disorders have risen to epidemic proportions globally and thus concomitantly increased the prevalence of the metabolic syndrome. Elevated circulating plasma triglyceride (TG) and total cholesterol (TC) concentrations are characteristic features often associated with the metabolic syndrome. Acyl-CoA:diacylglycerol acyltransferases (DGATs) catalyze the final and only dedicated step of TG biosynthesis. DGAT1 and DGAT2 are two known forms of DGAT enzymes. DGAT1 deficiency in mice results in a metabolically beneficial phenotype of resistance to diet-induced obesity and fatty liver disease and increased energy expenditure, which is reversed when DGAT1 is expressed only in the intestine. Furthermore, DGAT1 deficiency in apolipoprotein E-/- mice has an athero-protective role partially due to lower plasma cholesterol concentrations and reduced intestinal cholesterol absorption.In the first part of this thesis, we used intestine-specific DGAT1 knockout (IDGAT1-/-) mice to elucidate the contribution of intestinal DGAT1 (I-DGAT1) activity in TG and cholesterol homeostasis. Cholesterol absorption, as measured by acute and fractional cholesterol absorption assays, was severely reduced in the small intestine and liver of I-DGAT1-/-mice. When challenged with high-fat/high cholesterol diet, I-DGAT1-/- mice exhibit resistance to diet-induced obesity coupled with lower plasma TC and cholesteryl ester concentrations compared to control littermates. Observations of I-DGAT1 deficiency phenocopy findings in whole body DGAT1-/- and DGAT1 inhibitor-treated mice. The postprandial chylomicron metabolism is altered in I-DGAT1-/- mice as simultaneous gavage of [3H]triolein and [14C]cholesterol revealed a reduced chylomicron secretion rate and radiotracer counts in plasma and lymph chylomicrons. In addition, deficiency/inhibition of DGAT1 results in smaller chylomicron size and increased trans-intestinal cholesterol excretion. We show that the improved cholesterol phenotype is a result of decreased enterocyte cholesterol secretion and altered dietary FA metabolism. In summary our findings provide insight into a novel role of DGAT1 and identify a pathway by which I-DGAT1 deficiency affects whole-body cholesterol homeostasis in mice by altering chylomicron metabolism and increasing TICE. In the second part, we explored the contribution of DGAT enzymes in the maintenance of thermoregulation upon acute and chronic cold exposure. Circulating lipoproteins like chylomicrons play a significant role towards fuel replenishment in the brown adipose tissue during high energy demand conditions. Therefore, we determined whether reduced circulating cholesterol concentrations and smaller chylomicron size observed in I-DGAT1-/- mice affects thermoregulation upon acute or chronic cold exposure. We observed increased uptake of chylomicron-derived lipids in the BAT of cold-exposed I-DGAT1-/- mice. Furthermore, acute thermogenesis was slightly improved in I-DGAT1-/-mice but the adaptive thermogenesis was comparable between control and I-DGAT1-/- mice. In addition, using in vitro and in vivo pharmacological DGAT1 and DGAT2 inhibition studies, we determined that TG biosynthesis via DGAT enzymes in BAT is fundamental for the replenishment of the FA pool to sustain thermogenesis during shivering as well as non-shivering thermogenesis.