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Permanent link (DOI): https://doi.org/10.7939/R3P26Q847

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Physiological function of phosphatidylethanolamine N-methyltransferase Open Access

Descriptions

Other title
Subject/Keyword
ER stress
NASH
PEMT
obesity
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Gao, Xia
Supervisor and department
Rene´ L. Jacobs (department of Agricultural, Food & Nutritional Science)
Dennis E. Vance (department of Biochemistry)
Examining committee member and department
Rene´ L. Jacobs (department of Agricultural, Food & Nutritional Science, University of Alberta)
Joanne Lemieux (department of Biochemistry, University of Alberta)
Khosrow Adeli (Division of Clinical Biochemistry, The Hospital for Children at the University of Toronto)
Dennis E. Vance (department of Biochemistry, University of Alberta)
Carlos Fernandez-Patron (department of Biochemistry, University of Alberta)
Department
Department of Biochemistry
Specialization

Date accepted
2015-05-12T09:43:59Z
Graduation date
2015-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Phosphatidylethanolamine N-methyltransferase (PEMT), a liver enriched enzyme, is responsible for approximately one third of hepatic phosphatidylcholine (PC) biosynthesis via three sequential methylations of phosphatidylethanolamine (PE). PEMT is also expressed in white adipose tissue (WAT). When fed a high-fat diet (HF), Pemt-/-mice are protected from diet-induced obesity (DIO), but develop steatohepatitis. This thesis is endeavored to seek the underlying mechanisms for the resistance to DIO and the development of steatohepatitis in HF-fed Pemt-/- mice, mainly focusing on the liver, WAT and brown adipose tissue (BAT). The vagus nerve relays signals between the liver and brain, regulating energy metabolism. Thus, a possible role of the hepatic branch of the vagus nerve in the resistance to DIO and the development of steatohepatitis in Pemt-/- mice was first explored. Pemt-/- and Pemt+/+ mice were subjected to hepatic vagotomy (HV), compared with sham operation; or subjected to capsaicin treatment, which selectively disrupts the afferent nerve, versus vehicle-treated mice. After surgery, mice were fed the HF for 10 weeks. HV abolished the protection against DIO and prevented the development of steatohepatitis in Pemt-/- mice. However, disruption of the hepatic afferent vagus nerve by capsaicin failed to reverse either the protection against DIO or the development of HF-induced steatohepatitis in Pemt-/- mice. Thus, neuronal signals, relayed particularly via the efferent vagus nerve, contribute to the development of steatohepatitis and protection against obesity in HF-fed Pemt-/- mice. Endoplasmic reticulum (ER) stress is associated with the development and progression of steatohepatitis. PEMT is located on the ER and mitochondrial-associated membranes. Thus, we proposed that PEMT deficiency might cause aberrant composition of PC and PE in the ER and consequently ER stress, which sensitized mice to HF-induced steatohepatitis. Indeed, chow-fed Pemt-/- mice had reduced PC and increased PE in hepatic ER fractions. Chow-fed Pemt-/- mice presented ER stress in the livers with higher expression of CHOP and BIP compared to Pemt+/+ mice, without activating the unfolded protein response (UPR). HF led to more severe ER stress and activated UPR including all three branches PERK-eIF2α, IRE1α-XBP1s and ATF6, in the livers from Pemt-/- mice than Pemt+/+ mice. Similarly, McArdle cells without PEMT activity exhibited ER stress and activated UPR compared with McArdle cells expressing PEMT. Furthermore, the chemical chaperone 4-phenyl butyric acid (PBA) reversed the activation of UPR and ER stress caused by PEMT deficiency in McArdle cells. PBA had a minor impact on hepatic ER stress or the development of steatohepatisis in HF-fed Pemt-/- mice. However, PBA decreased triglyceride accumulation and alleviated apoptotic signaling in the livers from these mice. Together, PEMT deficiency leads to hepatic ER stress and sensitizes mice to HF-induced steatohepatitis. The contribution of WAT and BAT to the protection against DIO in Pemt-/- mice has also been studied. PEMT deficiency had no effect on adipocyte differentiation or lipolysis in WAT, but resulted in a decreased lipogenesis in WAT, which at least partially contributes to the lower weight gain in HF-fed Pemt-/- mice. Contrary to WAT, BAT is a highly oxidative tissue, responsible for non-shivering thermogenesis. In BAT, the protein and enzyme activity of PEMT was not detectable, compared to that in the liver or WAT. The capability for thermogenesis in mice was evaluated by cold exposure at 4˚C. When fed standard chow diet, both Pemt+/+ and Pemt-/- mice were able to maintain their body temperature above 33˚C for up to 4 h upon cold exposure. However, after fed the HF diet for 2 weeks, Pemt-/- mice developed hypothermia, whereas Pemt+/+ mice maintained their body temperature throughout the 4 h cold challenge. However, thermogenic capacity in BAT remained intact in HF-fed Pemt-/- mice. Dietary choline supplementation prevented the cold-induced hypothermia in Pemt-/- mice, coinciding with restoration of lower plasma glucose and increased expression of hepatic gluconeogenesis-related genes. Thus, cold-induced hypothermia in HF-fed Pemt-/- mice is likely due to an insufficient glucose supply caused by impaired hepatic gluconeogenesis, highlighting the importance of glucose as a substrate for thermogenesis.
Language
English
DOI
doi:10.7939/R3P26Q847
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Xia Gao, Jelske van der Veen, Linfu Zhu, Todd Chaba, Marta Ordoñez, Susanne Lingrell, Debby PY Koonen, Jason RB Dyck, Antonio Gomez-Muñoz, Dennis E. Vance and René L. Jacobs. Vagus nerve contributes to the development of steatohepatitis and obesity in Phosphatidylethanolamine N-Methyltransferase deficient mice. (2015) Journal of Hepatology. 62 (2015) 913-920.Xia Gao, Jelske N. van der Veen, Martin Hermansson, Marta Ordoñez, Antonio Gomez-Muñoz, Dennis E. Vance, René L. Jacobs. Decreased lipogenesis in white adipose tissue contributes to the resistance to high fat diet-induced obesity in phosphatidylethanolamine N-methyltransferase-deficient mice. (2015) Biochimica et Biophysica Acta (BBA)-molecular and cell biology of lipids. 1851 (2015) 152–162

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