The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue

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Qadri , S , Lallukka-Brück , S , Luukkonen , P K , Zhou , Y , Gastaldelli , A , Orho-Melander , M , Sammalkorpi , H , Juuti , A , Penttilä , A K , Perttilä , J , Hakkarainen , A , Lehtimäki , T E , Oresic , M , Hyötyläinen , T , Hodson , L , Olkkonen , V M & Yki-Järvinen , H 2020 , ' The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue ' , Liver International , vol. 40 , no. 9 , pp. 2128-2138 . https://doi.org/10.1111/liv.14507

Title: The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue
Author: Qadri, Sami; Lallukka-Brück, Susanna; Luukkonen, Panu K.; Zhou, You; Gastaldelli, Amalia; Orho-Melander, Marju; Sammalkorpi, Henna; Juuti, Anne; Penttilä, Anne K.; Perttilä, Julia; Hakkarainen, Antti; Lehtimäki, Tiina E.; Oresic, Matej; Hyötyläinen , Tuulia; Hodson, Leanne; Olkkonen, Vesa M.; Yki-Järvinen, Hannele
Contributor organization: University of Helsinki
Helsinki University Hospital Area
Department of Medicine
HUS Internal Medicine and Rehabilitation
HUS Abdominal Center
II kirurgian klinikka
Clinicum
Department of Surgery
HUS Medical Imaging Center
Department of Diagnostics and Therapeutics
Date: 2020-08-12
Language: eng
Number of pages: 11
Belongs to series: Liver International
ISSN: 1478-3223
DOI: https://doi.org/10.1111/liv.14507
URI: http://hdl.handle.net/10138/333732
Abstract: Background & Aims The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. Methods Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3(148MM/MI), n = 63; PNPLA3(148II), n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3(148MM), n = 25) or lacking the variant (PNPLA3(148II), n = 25). Whole-body insulin sensitivity of lipolysis was determined using [H-2(5)]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. Results PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P <.0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P <.0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P <.0001). Conclusions Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.
Subject: adipose tissue
fatty acids
lipidomics
lipolysis
non-alcoholic fatty liver disease
triglycerides
FATTY LIVER-DISEASE
DOMAIN-CONTAINING 3
GENETIC-VARIATION
INSULIN-RESISTANCE
ACIDS
ADIPONUTRIN
OBESITY
STEATOSIS
GLUCOSE
SUSCEPTIBILITY
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: acceptedVersion


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