Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Elevation of blood lipids in hepatocyte-specific fatty acid transport 4- deficient mice fed with high glucose diets Stephan Döring a , Jessica Seeßle a , Hongying Gan-Schreier a , Bahador Javaheri a , Li Jiao b , Yuting Cheng a , Sabine Tuma-Kellner a , Gerhard Liebisch c , Thomas Herrmann d , Wolfgang Stremmel a , Walee Chamulitrat a, ⁎ a Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany b Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, Yunnan 650118, China c Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany d Westkuesten Hospital, Esmarchstraße 50, 25746 Heide, Germany ARTICLE INFO Keywords: Fatty acid transport protein4 High-sugar diets Fatty acid metabolism Triglycerides Lipolysis ABSTRACT Fatty acid transport protein4 (FATP4) is upregulated in acquired and central obesity and its polymorphisms are associated with blood lipids and insulin resistance. Patients with FATP4 mutations and mice with global FATP4 deletion exhibit skin abnormalities characterized as ischthyosis prematurity syndrome (IPS). Cumulating data have shown that an absence of FATP4 increases the levels of cellular triglycerides (TG). However, FATP4 role and consequent lipid and TG metabolism in the hepatocyte is still elusive. Here, hepatocyte-specific FATP4 deficient (Fatp4 L-/- ) mice were generated. When fed with chow, these mutant mice displayed no phenotypes regarding blood lipids. However when fed low-fat/high-sugar (HS) or high-fat/high-sugar (HFS) for 12 weeks, Fatp4 L-/- mice showed a significant increase of plasma TG, free fatty acids and glycerol when compared with diet-fed control mice. Interestingly, Fatp4 L-/- mice under HS diet had lower body and liver weights and they were not protected from HFS-induced body weight gain and hepatic steatosis. Male mutant mice were more sensitive to HFS diet than female mutant mice. Glucose intolerance was observed only in female Fatp4 L-/- mice fed with HS diet. Lipidomics analyses revealed that hepatic phospholipids were not disturbed in mutant mice under both diets. Thus, hepatic FATP4 deletion rendered an increase of blood lipids including glycerol indicating a preferential fatty-acid channeling to TG pools that are specifically available for lipolysis. Our results imply a possible risk of hyperlipidemia as a result of abnormal metabolism in liver in IPS patients with FATP4 mutations who consume high-sugar diets. 1. Introduction The uptake, metabolism, and utilization of long-chain fatty acids (LCFA) are critical for physiological cellular processes. The dysregula- tion of these processes leads to the development of metabolic diseases including non-alcoholic steatohepatitis, diabetes, and insulin resistance [1]. Protein-mediated transport of LCFA by members of fatty acid transport proteins (FATPs) and long-chain acyl-CoA synthetases (ACSL) is thought to be a major mode of LCFA uptake and activation [2,3]. For the liver, plasma membrane FATP5 mediates fatty-acid uptake con- tributing to obesity and hepatic steatosis [4]. Whereas other FATPs, such as FATP4 [5] which is localized in the endoplasmic reticulum (ER), do not transport fatty acids across plasma membrane [6] but mediate vectorial acylation of fatty acids hence indirectly driving the uptake [5,6]. Another consequence of fatty-acid acylation is that dis- tinct classes of fatty acids are trafficked into different metabolic pools https://doi.org/10.1016/j.ymgme.2018.11.010 Received 7 September 2018; Received in revised form 12 November 2018; Accepted 17 November 2018 Abbreviations: ACSL, long-chain acyl-CoA-synthetases; Agpat2, 1-acylglycerol-3-phosphate-O-acyltransferase; ALT, alanine aminotransferase; AST, aspartate ami- notransferase; ATGL, adipose triglyceride lipase; Cer, ceramides; DGAT, diacylglycerol acyltransferase; ER, endoplasmic reticulum; ESI-MS/MS, electrospray ioni- zation tandem mass spectrometry; FABP, fatty acid binding protein; FATP, fatty acid transport protein; FFA, free fatty acids; GC–MS, gas chromatography mass spectrometry; GPAT, glycerol 3-phosphate acyl transferase; GTT, glucose tolerance test; H&E, hematoxylin and eosin; HFS, high-fat/high-sugar; HS, high-sugar; IPS, ichthyosis prematurity syndrome; ITT, insulin tolerance test; LCFA, long-chain fatty acids; LC/MS-MS, liquid chromatography mass spectrometry; LDH, lactate dehydrogenase; Lxr, liver X receptor; MUFA, monounsaturated fatty acids; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PPAR, peroxisome-proliferator activated receptors; PS, phosphatidylserine; SM, sphingomyelin; TG, triglycerides ⁎ Corresponding author: Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 345, EG, 69120 Heidelberg, Germany. E-mail address: Walee.Chamulitrat@med.uni-heidelberg.de (W. Chamulitrat). Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx 1096-7192/ © 2018 Elsevier Inc. All rights reserved. Please cite this article as: Döring, S., Molecular Genetics and Metabolism, https://doi.org/10.1016/j.ymgme.2018.11.010