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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries with an estimated 80% of cases in the morbidly obese population and approximately 20– 30% in the general population [1]
Hepatic fat accumulation in the absence of other liver diseases is manifest as simple steatosis (SS) in most individuals with NAFLD, concomitant necroinflammatory changes may result in a minority (3–5%); these histologic features are termed nonalcoholic steatohepatitis (NASH)
Anthropomorphic Measurements The presence of steatosis, ballooning, inflammation and fibrosis was determined by a hepatopathologist using two independent histologic specimens for classification and subsequent scoring by the NAFLD Activity Score (NAS) [29]
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries with an estimated 80% of cases in the morbidly obese population and approximately 20– 30% in the general population [1]. Few of these findings have been demonstrated directly in humans and little is known regarding how lipid zonation changes with disease, diet or environmental challenge. Insight into the distribution of some hepatic lipid species was recently established by Debois et al in normal and SS human liver specimens using cluster TOF-SIMS imaging [21] They demonstrated periportal enrichment of a-tocopherol and cholesterol, along with a macrovesicular enrichment of TAGs, DAGs and FAs. the TOF-SIMS is a hard ionization technology resulting in significant lipid fragmentation, hampering the detection and discrimination of intact phospholipids. We examined the in situ hepatic localization of an important enzyme in the phosphatidylcholine biosynthetic pathway, PEMT, to investigate if altered zonation of PC biosynthetic enzymes may contribute to NAFLD progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
