PMID- 37198225
OWN - NLM
STAT- MEDLINE
DCOM- 20230607
LR  - 20240320
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 May 17
TI  - Liver-specific overexpression of HKDC1 increases hepatocyte size and 
      proliferative capacity.
PG  - 8034
LID - 10.1038/s41598-023-33924-3 [doi]
LID - 8034
AB  - A primary role of the liver is to regulate whole body glucose homeostasis. 
      Glucokinase (GCK) is the main hexokinase (HK) expressed in hepatocytes and 
      functions to phosphorylate the glucose that enters via GLUT transporters to 
      become glucose-6-phosphate (G6P), which subsequently commits glucose to enter 
      downstream anabolic and catabolic pathways. In the recent years, hexokinase 
      domain-containing-1 (HKDC1), a novel 5th HK, has been characterized by our group 
      and others. Its expression profile varies but has been identified to have low 
      basal expression in normal liver but increases during states of stress including 
      pregnancy, nonalcoholic fatty liver disease (NAFLD), and liver cancer. Here, we 
      have developed a stable overexpression model of hepatic HKDC1 in mice to examine 
      its effect on metabolic regulation. We found that HKDC1 overexpression, over 
      time, causes impaired glucose homeostasis in male mice and shifts glucose 
      metabolism towards anabolic pathways with an increase in nucleotide synthesis. 
      Furthermore, we observed these mice to have larger liver sizes due to greater 
      hepatocyte proliferative potential and cell size, which in part, is mediated via 
      yes-associated protein (YAP) signaling.
CI  - (c) 2023. This is a U.S. Government work and not under copyright protection in the 
      US; foreign copyright protection may apply.
FAU - Pusec, Carolina M
AU  - Pusec CM
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Ilievski, Vladimir
AU  - Ilievski V
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - De Jesus, Adam
AU  - De Jesus A
AD  - Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
FAU - Farooq, Zeenat
AU  - Farooq Z
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Zapater, Joseph L
AU  - Zapater JL
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
AD  - Jesse Brown VA Medical Center, Chicago, IL, USA.
FAU - Sweis, Nadia
AU  - Sweis N
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Ismail, Hagar
AU  - Ismail H
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Khan, Md Wasim
AU  - Khan MW
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Ardehali, Hossein
AU  - Ardehali H
AD  - Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
FAU - Cordoba-Chacon, Jose
AU  - Cordoba-Chacon J
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA.
FAU - Layden, Brian T
AU  - Layden BT
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Illinois at Chicago, Chicago, IL, USA. blayde1@uic.edu.
AD  - Jesse Brown VA Medical Center, Chicago, IL, USA. blayde1@uic.edu.
LA  - eng
GR  - P30 DK020595/DK/NIDDK NIH HHS/United States
GR  - R01 HL138982/HL/NHLBI NIH HHS/United States
GR  - R01 DK104927/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230517
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - EC 2.7.1.2 (Glucokinase)
RN  - IY9XDZ35W2 (Glucose)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.1.1 (Hkdc1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Male
MH  - Mice
MH  - Glucokinase/metabolism
MH  - Glucose/metabolism
MH  - Hepatocytes/metabolism
MH  - *Hexokinase/genetics/metabolism
MH  - Liver/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
PMC - PMC10192376
COIS- The authors declare no competing interests.
EDAT- 2023/05/18 01:07
MHDA- 2023/05/19 06:41
PMCR- 2023/05/17
CRDT- 2023/05/17 23:19
PHST- 2022/08/19 00:00 [received]
PHST- 2023/04/20 00:00 [accepted]
PHST- 2023/05/19 06:41 [medline]
PHST- 2023/05/18 01:07 [pubmed]
PHST- 2023/05/17 23:19 [entrez]
PHST- 2023/05/17 00:00 [pmc-release]
AID - 10.1038/s41598-023-33924-3 [pii]
AID - 33924 [pii]
AID - 10.1038/s41598-023-33924-3 [doi]
PST - epublish
SO  - Sci Rep. 2023 May 17;13(1):8034. doi: 10.1038/s41598-023-33924-3.