Nonalcoholic fatty liver disease in CLOCK mutant mice

Area of Science:

• Hepatology
• Molecular Biology
• Chronobiology

Background:

• Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern linked to rising obesity rates.
• The role of circadian rhythm disruption in NAFLD pathogenesis remains incompletely understood.

Purpose of the Study:

• To investigate the impact of a mutated circadian locomotor output cycles kaput (CLOCK) protein on hepatic lipid metabolism and NAFLD development.
• To elucidate the molecular mechanisms linking circadian regulation, hypoxia, and fatty acid metabolism in NAFLD.

Main Methods:

• Utilized C57BL/6 Clkwt/wt and apolipoprotein E-deficient (Apoe-/-) mice with a CLOCK mutation (ClkΔ19/Δ19).
• Challenged mice with Western diet, lipopolysaccharide, or CoCl2 to induce liver disease.
• Analyzed protein expression of CD36 and hypoxia-inducible factor 1α (HIF1α), and CLOCK protein interactions with PHD protein promoters.

Main Results:

• ClkΔ19/Δ19 mice, including Apoe-/- double mutants, developed a spectrum of liver diseases mirroring human NAFLD.
• Identified increased CD36 and HIF1α protein levels as key factors in NAFLD development.
• Demonstrated that mutated CLOCK leads to reduced PHD levels, elevated HIF1α, and subsequent enhanced fatty acid uptake via CD36.

Conclusions:

• Established a regulatory connection between circadian rhythms, hypoxia response, fatty acid uptake, and NAFLD.
• The developed mouse models offer valuable tools for further NAFLD research and therapeutic drug discovery.