Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the western world, with spectrum from simple steatosis to non-alcoholic steatohepatitis, which can progress to cirrhosis. NAFLD developments are known to be affected by host genetic background. Herein we emphasize the power of collaborative cross (CC) mouse for dissecting this complex trait and revealing quantitative trait loci (QTL) controlling hepatic fat accumulation in mice. 168 female and 338 male mice from 24 and 37 CC lines, respectively, of 18–20 weeks old, maintained on standard rodent diet, since weaning. Hepatic fat content was assessed, using dual DEXA scan in the liver. Using the available high-density genotype markers of the CC line, QTL mapping associated with percentage liver fat accumulation was performed. Our results revealed significant fatty liver accumulation QTL that were specifically, mapped in females. Two significant QTLs on chromosomes 17 and 18, with genomic intervals 3 and 2 Mb, respectively, were mapped. A third QTL, with a less significant P value, was mapped to chromosome 4, with genomic interval of 2 Mb. These QTLs were named Flal1–Flal3, referring to Fatty Liver Accumulation Locus 1–3, for the QTLs on chromosomes 17, 18, and 4, respectively. Unfortunately, no QTL was mapped with males. Searching the mouse genome database suggested several candidate genes involved in hepatic fat accumulation. Our results show that susceptibility to hepatic fat accumulations is a complex trait, controlled by multiple genetic factors in female mice, but not in male.
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Acknowledgments
The present work is part of a Ph.D. thesis by Hanifa J. Atamni theses. The authors declare no competing financial interests or other associations that might pose a conflict of interest (e.g., pharmaceutical stock ownership, consultancy). This work was supported by the Hendrech and EiranGotwert Fund for studying diabetes, Wellcome Trust grants 085906/Z/08/Z, 075491/Z/04, Wellcome Trust core funding grant 090532/Z/09/Z, and core funding by Tel Aviv University. This work was supported by the Israeli Centers of Research Excellence (I-CORE): Center No. 41/11 (MB, I.G-V) and a fellowship from the Edmond J. Safra Center for Bioinformatics at Tel Aviv University (MB).
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The authors declare no potential conflict of interest with respect to financial or non-financial competing interests, the authorship, and/or publication of this article, e.g., pharmaceutical stock ownership and consultancy.
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H. J. A. -T. Atamni and M. Botzman have equal contribution.
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Atamni, H.J.AT., Botzman, M., Mott, R. et al. Mapping liver fat female-dependent quantitative trait loci in collaborative cross mice. Mamm Genome 27, 565–573 (2016). https://doi.org/10.1007/s00335-016-9658-3
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DOI: https://doi.org/10.1007/s00335-016-9658-3