Hepatic HKDC1 expression contributes to liver metabolism

Carolina M. Pusec, Adam De Jesus, Md Wasim Khan, Alexander R. Terry, Anton E. Ludvik, Kai Xu, Nicholas Giancola, Haaris Pervaiz, Emily Daviau Smith, Xianzhong Ding, Stephen Harrison, Navdeep Chandel, Thomas C. Becker, Nissim Hay, Hossein Ardehali, Jose Cordoba-Chacon, Brian T. Layden*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)313-330
Number of pages18
JournalEndocrinology
Volume160
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Liver
Hexokinase
Hepatocytes
Glucose
Mitochondrial Dynamics
Glucokinase
Mitochondrial Membrane Potential
Lipid Metabolism
Liver Cirrhosis
Mitochondria
Respiration
Triglycerides
Homeostasis
Diet
Inflammation
Non-alcoholic Fatty Liver Disease

ASJC Scopus subject areas

  • Endocrinology

Cite this

Pusec, C. M., De Jesus, A., Khan, M. W., Terry, A. R., Ludvik, A. E., Xu, K., ... Layden, B. T. (2019). Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology, 160(2), 313-330. https://doi.org/10.1210/en.2018-00887
Pusec, Carolina M. ; De Jesus, Adam ; Khan, Md Wasim ; Terry, Alexander R. ; Ludvik, Anton E. ; Xu, Kai ; Giancola, Nicholas ; Pervaiz, Haaris ; Smith, Emily Daviau ; Ding, Xianzhong ; Harrison, Stephen ; Chandel, Navdeep ; Becker, Thomas C. ; Hay, Nissim ; Ardehali, Hossein ; Cordoba-Chacon, Jose ; Layden, Brian T. / Hepatic HKDC1 expression contributes to liver metabolism. In: Endocrinology. 2019 ; Vol. 160, No. 2. pp. 313-330.
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abstract = "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.",
author = "Pusec, {Carolina M.} and {De Jesus}, Adam and Khan, {Md Wasim} and Terry, {Alexander R.} and Ludvik, {Anton E.} and Kai Xu and Nicholas Giancola and Haaris Pervaiz and Smith, {Emily Daviau} and Xianzhong Ding and Stephen Harrison and Navdeep Chandel and Becker, {Thomas C.} and Nissim Hay and Hossein Ardehali and Jose Cordoba-Chacon and Layden, {Brian T.}",
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Pusec, CM, De Jesus, A, Khan, MW, Terry, AR, Ludvik, AE, Xu, K, Giancola, N, Pervaiz, H, Smith, ED, Ding, X, Harrison, S, Chandel, N, Becker, TC, Hay, N, Ardehali, H, Cordoba-Chacon, J & Layden, BT 2019, 'Hepatic HKDC1 expression contributes to liver metabolism', Endocrinology, vol. 160, no. 2, pp. 313-330. https://doi.org/10.1210/en.2018-00887

Hepatic HKDC1 expression contributes to liver metabolism. / Pusec, Carolina M.; De Jesus, Adam; Khan, Md Wasim; Terry, Alexander R.; Ludvik, Anton E.; Xu, Kai; Giancola, Nicholas; Pervaiz, Haaris; Smith, Emily Daviau; Ding, Xianzhong; Harrison, Stephen; Chandel, Navdeep; Becker, Thomas C.; Hay, Nissim; Ardehali, Hossein; Cordoba-Chacon, Jose; Layden, Brian T.

In: Endocrinology, Vol. 160, No. 2, 01.01.2019, p. 313-330.

Research output: Contribution to journalArticle

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T1 - Hepatic HKDC1 expression contributes to liver metabolism

AU - Pusec, Carolina M.

AU - De Jesus, Adam

AU - Khan, Md Wasim

AU - Terry, Alexander R.

AU - Ludvik, Anton E.

AU - Xu, Kai

AU - Giancola, Nicholas

AU - Pervaiz, Haaris

AU - Smith, Emily Daviau

AU - Ding, Xianzhong

AU - Harrison, Stephen

AU - Chandel, Navdeep

AU - Becker, Thomas C.

AU - Hay, Nissim

AU - Ardehali, Hossein

AU - Cordoba-Chacon, Jose

AU - Layden, Brian T.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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Pusec CM, De Jesus A, Khan MW, Terry AR, Ludvik AE, Xu K et al. Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology. 2019 Jan 1;160(2):313-330. https://doi.org/10.1210/en.2018-00887