PMID- 30517626 OWN - NLM STAT- MEDLINE DCOM- 20191203 LR - 20240408 IS - 1945-7170 (Electronic) IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 160 IP - 2 DP - 2019 Feb 1 TI - Hepatic HKDC1 Expression Contributes to Liver Metabolism. PG - 313-330 LID - 10.1210/en.2018-00887 [doi] AB - Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed HK domain-containing 1 (HKDC1) to be a fifth HK with expression in the liver. Here, we reveal HKDC1 to have low glucose-phosphorylating ability and demonstrate its association with the mitochondria in hepatocytes. As we have shown previously that genetic deletion of HKDC1 leads to altered hepatic triglyceride levels, we also explored the influence of overexpression of HKDC1 in hepatocytes on cellular metabolism, observing reduced glycolytic capacity and maximal mitochondrial respiration with concurrent reductions in glucose oxidation and mitochondrial membrane potential. Furthermore, we found that acute in vivo overexpression of HKDC1 in the liver induced substantial changes in mitochondrial dynamics. Altogether, these findings suggest that overexpression of HKDC1 causes mitochondrial dysfunction in hepatocytes. However, its overexpression was not enough to alter energy storage in the liver but led to mild improvement in glucose tolerance. We next investigated the conditions necessary to induce HKDC1 expression, observing HKDC1 expression to be elevated in human patients whose livers were at more advanced stages of nonalcoholic fatty liver disease (NAFLD) and similarly, found high liver expression in mice on diets causing high levels of liver inflammation and fibrosis. Overall, our data suggest that HKDC1 expression in hepatocytes results in defective mitochondrial function and altered hepatocellular metabolism and speculate that its expression in the liver may play a role in the development of NAFLD. FAU - Pusec, Carolina M AU - Pusec CM AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - De Jesus, Adam AU - De Jesus A AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Khan, Md Wasim AU - Khan MW AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. FAU - Terry, Alexander R AU - Terry AR AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. FAU - Ludvik, Anton E AU - Ludvik AE AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Xu, Kai AU - Xu K AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. FAU - Giancola, Nicholas AU - Giancola N AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Pervaiz, Haaris AU - Pervaiz H AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Daviau Smith, Emily AU - Daviau Smith E AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Ding, Xianzhong AU - Ding X AD - Department of Pathology, Loyola University Chicago, Maywood, Illinois. FAU - Harrison, Stephen AU - Harrison S AD - Brooke Army Medical Center, San Antonio, Texas. FAU - Chandel, Navdeep S AU - Chandel NS AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Becker, Thomas C AU - Becker TC AD - Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, North Carolina. AD - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina. FAU - Hay, Nissim AU - Hay N AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. FAU - Ardehali, Hossein AU - Ardehali H AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Cordoba-Chacon, Jose AU - Cordoba-Chacon J AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. FAU - Layden, Brian T AU - Layden BT AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. AD - Northwestern University Feinberg School of Medicine, Chicago, Illinois. AD - Jesse Brown VA Medical Center, Chicago, Illinois. LA - eng GR - K01 DK115525/DK/NIDDK NIH HHS/United States GR - R01 HL138982/HL/NHLBI NIH HHS/United States GR - R01 CA206167/CA/NCI NIH HHS/United States GR - P01 AG049665/AG/NIA NIH HHS/United States GR - T32 GM008152/GM/NIGMS NIH HHS/United States GR - P30 DK020595/DK/NIDDK NIH HHS/United States GR - F30 CA225058/CA/NCI NIH HHS/United States GR - R01 DK104927/DK/NIDDK NIH HHS/United States GR - R01 HL127646/HL/NHLBI NIH HHS/United States GR - IK2 BX001587/BX/BLRD VA/United States GR - T32 DK007169/DK/NIDDK NIH HHS/United States GR - R25 GM079300/GM/NIGMS NIH HHS/United States GR - I01 BX000733/BX/BLRD VA/United States GR - T32 GM144295/GM/NIGMS NIH HHS/United States GR - I01 BX003382/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - EC 2.7.1.1 (Hexokinase) RN - EC 2.7.1.1 (Hkdc1 protein, mouse) SB - IM MH - Amino Acid Sequence MH - Animals MH - Energy Metabolism MH - Female MH - Glucose Tolerance Test MH - Glycolysis MH - Hepatocytes/enzymology MH - Hexokinase/*metabolism MH - Humans MH - Liver/*metabolism MH - Male MH - Mice MH - Mitochondria, Liver/enzymology MH - Non-alcoholic Fatty Liver Disease/etiology PMC - PMC6334269 EDAT- 2018/12/06 06:00 MHDA- 2019/12/04 06:00 PMCR- 2019/12/03 CRDT- 2018/12/06 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2018/11/16 00:00 [accepted] PHST- 2018/12/06 06:00 [pubmed] PHST- 2019/12/04 06:00 [medline] PHST- 2018/12/06 06:00 [entrez] PHST- 2019/12/03 00:00 [pmc-release] AID - 5224519 [pii] AID - endo_201800887 [pii] AID - 10.1210/en.2018-00887 [doi] PST - ppublish SO - Endocrinology. 2019 Feb 1;160(2):313-330. doi: 10.1210/en.2018-00887.