title: Differential intrahepatic phospholipid zonation in simple steatosis and nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34:1 and PC 36:2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH.
authors: Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, United States of America.
authors: Julia
authors: J
authors: Wattacheril
authors: Erin H
authors: EH
authors: Seeley
authors: Peggi
authors: P
authors: Angel
authors: Heidi
authors: H
authors: Chen
authors: Benjamin P
authors: BP
authors: Bowen
authors: Christian
authors: C
authors: Lanciault
authors: Richard M
authors: RM
authors: Caprioli
authors: Naji
authors: N
authors: Abumrad
authors: Charles Robb
authors: CR
authors: Flynn
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D010743:Phospholipids / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D010743:Phospholipids