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Mol Metab.2020 Jul;:101051. S2212-8778(20)30125-3. doi: 10.1016/j.molmet.2020.101051.Epub 2020-07-09.


Liver-specific Prkn knockout mice are more susceptible to diet-induced hepatic steatosis and insulin resistance.

  • Lia R Edmunds
  • Bingxian Xie
  • Amanda M Mills
  • Brydie R Huckestein
  • Ramya Undamatla
  • Anjana Murali
  • Martha M Pangburn
  • James Martin
  • Ian Sipula
  • Brett A Kaufman
  • Iain Scott
  • Michael J Jurczak
PMID: 32653576 DOI: 10.1016/j.molmet.2020.101051.




OBJECTIVE: PARKIN is an E3 ubiquitin ligase that regulates mitochondrial quality control through a process called mitophagy. Recent human and rodent studies suggest that loss of hepatic mitophagy may occur during the pathogenesis of obesity-associated fatty liver and contribute to changes in mitochondrial metabolism associated with this disease. Whole-body Prkn knockout mice are paradoxically protected against diet-induced hepatic steatosis; however, liver-specific effects of Prkn deficiency cannot be discerned in this model due to pleotropic effects of germline Prkn deletion on energy balance and subsequent protection against diet-induced obesity. We therefore generated the first liver-specific Prkn knockout mouse strain (LKO) to directly address the role of hepatic Prkn.


後期対照(WT)とLKOマウスに通常の飼料(RC)または高脂肪食(HFD)を与え、体重と体組成の経時変化を測定した。肝臓のミトコンドリア含量は複数の補完的な手法を用いて評価し、ミトコンドリア呼吸能力はオロボロス OK プラットフォームを用いて評価した。肝脂肪は生化学的に測定し、組織学的に評価し、肝遺伝子発現のグローバルな変化は RNA-seq で測定した。全身および組織特異的なインスリン抵抗性は、同位体トレーサーを用いた高インスリン血症性高ユーグリセミッククランプにより評価した。

METHODS: Littermate control (WT) and LKO mice were fed regular chow (RC) or high-fat diet (HFD) and changes in body weight and composition were measured over time. Liver mitochondrial content was assessed using multiple, complementary techniques and mitochondrial respiratory capacity assessed using Oroboros OK platform. Liver fat was measured biochemically and assessed histologically, while global changes in hepatic gene expression were measured by RNA-seq. Whole-body and tissue-specific insulin resistance were assessed by hyperinsulinemic euglycemic clamp with isotopic tracers.


Prknの肝臓特異的欠失は、RCまたはHFD給餌時の体重や脂肪率に影響を与えなかったが、肝性ステアトーシスはHFD給餌したLKOではWTマウスと比較して45%増加した(P<0.05)。いずれの食餌でも遺伝子型間のミトコンドリア含有量に差はなかったが、LKOマウスではミトコンドリアの呼吸能力と肝臓の効率が有意に低下していた。肝臓RNA-seqの結果から遺伝子エンリッチメント解析を行ったところ、脂質代謝と線維化に関連する経路に有意な変化が示唆された。最後に、全身インスリン感受性は、HFD 飼育 LKO マウスで 35%低下し(P<0.05)、これは主に肝インスリン抵抗性の増加によるものであった(全身効果の 60%、P=0.11)。

RESULTS: Liver-specific deletion of Prkn had no effect on body weight or adiposity during RC or HFD feeding, however, hepatic steatosis was increased by 45% in HFD-fed LKO compared with WT mice (P<0.05). While there were no differences in mitochondrial content between genotypes on either diet, mitochondrial respiratory capacity and efficiency in liver were significantly reduced in LKO mice. Gene enrichment analyses from liver RNA-seq results suggested significant changes in pathways related to lipid metabolism and fibrosis in HFD-fed Prkn knockout mice. Finally, whole-body insulin sensitivity was reduced by 35% in HFD-fed LKO mice (P<0.05), which was primarily due to increased hepatic insulin resistance (60% of whole-body effect; P=0.11).



CONCLUSIONS: These data demonstrate that PARKIN contributes to mitochondrial homeostasis in liver and plays a protective role against the pathogenesis of hepatic steatosis and insulin resistance.

Copyright © 2020. Published by Elsevier GmbH.