@article{9361abc094eb48ba9c7f8044e4cb84f8,
title = "Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease",
abstract = "Background & Aims: Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD. Methods: In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model. Results: There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids. Conclusions: We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.",
keywords = "Diacylglycerols, Lipidomics, Mixed Meal, NAFLD, Postprandial Lipids",
author = "Velenosi, {Thomas J.} and Gil Ben-Yakov and Podszun, {Maren C.} and Julian Hercun and Ohad Etzion and Shanna Yang and Cathy Nadal and Vanessa Haynes-Williams and Huang, {Wen Chun A.} and Lila Gonz{\'a}lez-H{\'o}dar and Brychta, {Robert J.} and Shogo Takahashi and Vikas Akkaraju and Krausz, {Kristopher W.} and Mary Walter and Hongyi Cai and Walter, {Peter J.} and Ranganath Muniyappa and Chen, {Kong Y.} and Gonzalez, {Frank J.} and Yaron Rotman",
note = "Funding Information: Funding The study was funded by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Center for Cancer Research, National Cancer Institute. Thomas J. Velenosi was supported by the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship.The graphical abstract was created with Biorender.com. We thank Drs Robert Shamburek and Lita Freeman for assistance in separating very low density lipoproteins, Dr Oksana Gavrilova for advice, and John Buckley for technical assistance. We are indebted to the study participants and the NIH Clinical Center staff for their support. All data and code are available from the corresponding author on request. Order of Authors (with Contributor Roles):, Thomas J. Velenosi, PhD (Formal analysis: Lead; Investigation: Lead; Methodology: Equal; Writing – original draft: Equal; Writing – review & editing: Equal), Gil Ben-Yakov, MD (Formal analysis: Supporting; Investigation: Equal; Writing – review & editing: Equal), Maren C. Podszun, PhD (Formal analysis: Supporting; Investigation: Equal; Methodology: Equal; Writing – original draft: Supporting; Writing – review & editing: Equal), Julian Hercun, MD (Formal analysis: Equal; Investigation: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal), Ohad Etzion, MD (Conceptualization: Supporting; Methodology: Supporting; Writing – review & editing: Equal), Shanna Yang, MPH, RD (Investigation: Supporting; Writing – review & editing: Equal), Cathy Nadal, RN (Investigation: Supporting; Writing – review & editing: Equal), Vanessa Haynes-Williams, RN, PhD (Investigation: Supporting; Writing – review & editing: Equal), Wen-Chun A. Huang, MSN (Investigation: Supporting; Writing – review & editing: Equal), Lila Gonz{\'a}lez-H{\'o}dar, PhD (Investigation: Supporting; Writing – review & editing: Equal), Robert J. Brychta, PhD (Investigation: Supporting; Writing – review & editing: Equal), Shogo Takahashi, PhD (Investigation: Supporting; Writing – review & editing: Equal), Vikas Akkaraju, BS (Investigation: Supporting; Writing – review & editing: Equal), Kristopher W. Krausz, MS (Investigation: Supporting; Writing – review & editing: Equal), Mary Walter, PhD (Investigation: Supporting; Writing – review & editing: Equal), Hongyi Cai, PhD (Investigation: Supporting; Writing – review & editing: Equal), Peter J. Walter, PhD (Investigation: Supporting; Methodology: Equal; Writing – review & editing: Equal), Ranganath Muniyappa, MD (Investigation: Supporting; Writing – review & editing: Equal), Kong Y. Chen, PhD (Investigation: Supporting; Writing – review & editing: Equal), Frank J. Gonzalez, PhD (Funding acquisition: Equal; Supervision: Supporting; Writing – review & editing: Equal), Yaron Rotman, MD, MSc (Conceptualization: Lead; Formal analysis: Equal; Funding acquisition: Equal; Supervision: Lead; Writing – original draft: Equal; Writing – review & editing: Lead) Funding Information: Funding The study was funded by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Center for Cancer Research, National Cancer Institute . Thomas J. Velenosi was supported by the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jun,
day = "1",
doi = "10.1053/j.gastro.2022.03.004",
language = "English",
volume = "162",
pages = "1990--2003",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "7",
}