title: Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
abstract: The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Suneng
authors.initials: S
authors.lastname: Fu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Oliver
authors.initials: O
authors.lastname: Hofmann
authors.forename: Lee
authors.initials: L
authors.lastname: Dicker
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
authors.forename: Steven M
authors.initials: SM
authors.lastname: Watkins
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Ivanov
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D020738:Leptin / Q000172:deficiency; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010713:Phosphatidylcholines / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D010714:Phosphatidylethanolamines / Q000378:metabolism; D014176:Protein Biosynthesis; D040901:Proteomics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013312:Stress, Physiological; D013851:Thinness / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D020738:Leptin; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium