계명대학교 의학도서관 Repository

Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization

Metadata Downloads
Author(s)
Ah-Reum OhYelin JeongJunjie YuDao Thi Minh TamJin Ku KangYoung Hoon JungSeung-Soon ImSang Bae LeeDongryeol RyuUtpal B PajvaniKyeongJin Kim
Keimyung Author(s)
Im, Seung Soon
Department
Dept. of Physiology (생리학)
Journal Title
Gastroenterology
Issued Date
2023
Volume
164
Issue
3
Keyword
ChrebpKctd17NAFLDType 2 Diabetes
Abstract
Background & aims:
Obesity predisposes to type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), but underlying mechanisms are incompletely understood. Potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in livers from obese mice and humans. In this study, we investigated the mechanism of increased Kctd17 and whether it is causal to obesity-induced metabolic complications.

Methods:
We transduced Rosa26-LSL-Cas9 knockin mice with AAV8-TBG-Cre (Control), AAV8-U6-Kctd17 sgRNA-TBG-Cre (L-Kctd17), AAV8-U6-Oga sgRNA-TBG-Cre (L-Oga), or AAV8-U6-Kctd17/Oga sgRNA-TBG-Cre (DKO). We fed mice a high-fat diet (HFD) and assessed for hepatic glucose and lipid homeostasis. We generated Kctd17, O-GlcNAcase (Oga), or Kctd17/Oga-knockout hepatoma cells by CRISPR-Cas9, and Kctd17-directed antisense oligonucleotide to test therapeutic potential in vivo. We analyzed transcriptomic data from patients with NAFLD.

Results:
Hepatocyte Kctd17 expression was increased in HFD-fed mice due to increased Srebp1c activity. HFD-fed L-Kctd17 or Kctd17 antisense oligonucleotide-treated mice show improved glucose tolerance and hepatic steatosis, whereas forced Kctd17 expression caused glucose intolerance and hepatic steatosis even in lean mice. Kctd17 induced Oga degradation, resulting in increasing carbohydrate response element-binding protein (Chrebp) protein, so concomitant Oga knockout negated metabolic benefits of hepatocyte Kctd17 deletion. In patients with NAFLD, KCTD17 messenger RNA was positively correlated with expression of Chrebp target and other lipogenic genes.

Conclusions:
Srebp1c-induced hepatocyte Kctd17 expression in obesity disrupted glucose and lipid metabolism by stabilizing Chrebp, and may represent a novel therapeutic target for obesity-induced T2D and NAFLD.
Keimyung Author(s)(Kor)
임승순
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
1528-0012
Source
https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S0016508522012951?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0016508522012951%3Fshowall%3Dtrue&referrer=https:%2F%2Fpubmed.ncbi.nlm.nih.gov%2F
DOI
10.1053/j.gastro.2022.11.019
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44759
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
공개 및 라이선스
  • 공개 구분공개
  • 엠바고Forever
파일 목록
  • 관련 파일이 존재하지 않습니다.

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.