Hepatic HKDC1 Expression Contributes to Liver Metabolism

Area of Science:

• Hepatology
• Mitochondrial Biology
• Metabolic Regulation

Background:

• Glucokinase (GCK) is the primary liver hexokinase, regulating glucose metabolism and lipid homeostasis.
• HKDC1 was recently identified as a potential fifth hexokinase expressed in the liver.

Purpose of the Study:

• To investigate the role and function of HKDC1 in liver cells.
• To determine the impact of HKDC1 overexpression on cellular metabolism and mitochondrial function.
• To explore the correlation between HKDC1 expression and nonalcoholic fatty liver disease (NAFLD).

Main Methods:

• Assessed glucose-phosphorylating ability of HKDC1.
• Examined HKDC1 localization within hepatocytes.
• Studied the effects of HKDC1 overexpression on glycolytic capacity, mitochondrial respiration, and glucose oxidation in vitro.
• Analyzed changes in mitochondrial dynamics in vivo following HKDC1 overexpression.
• Correlated HKDC1 liver expression with NAFLD stages in human patients and mouse models.

Main Results:

• HKDC1 exhibits low glucose-phosphorylating ability and associates with mitochondria.
• Overexpression of HKDC1 reduces glycolytic capacity, maximal mitochondrial respiration, glucose oxidation, and mitochondrial membrane potential.
• Acute in vivo HKDC1 overexpression alters hepatic mitochondrial dynamics.
• HKDC1 overexpression leads to mild improvements in glucose tolerance but does not alter energy storage.
• HKDC1 expression is elevated in advanced NAFLD and in mice with diet-induced liver inflammation and fibrosis.

Conclusions:

• Overexpression of HKDC1 induces mitochondrial dysfunction and alters hepatocellular metabolism.
• Elevated hepatic HKDC1 expression may contribute to the pathogenesis of NAFLD.
• HKDC1's role in liver metabolism warrants further investigation, particularly in the context of metabolic diseases.