Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function

Area of Science:

• Cellular Metabolism
• Epigenetics
• Molecular Biology

Background:

• AMP-activated protein kinase (AMPK) is crucial for energy homeostasis, but its in vivo regulation remains unclear.
• UHRF1 is an epigenetic regulator found in proliferating and cancer cells.

Purpose of the Study:

• To investigate the role of UHRF1 in regulating AMPK activity in vivo.
• To elucidate the mechanism by which UHRF1 controls AMPK function.
• To determine the physiological significance of UHRF1-mediated AMPK regulation in metabolism.

Main Methods:

• Co-immunoprecipitation to study UHRF1-AMPK interaction.
• Western blotting to assess AMPK phosphorylation and activity.
• Nuclear and cytoplasmic fractionation to determine AMPK localization.
• In vivo studies using mouse models with hepatic UHRF1 overexpression or adipose tissue UHRF1 knockdown.
• Analysis of glucose and lipid metabolism markers.

Main Results:

• UHRF1 interacts with AMPK and suppresses its activity under basal and stressed conditions.
• UHRF1 promotes AMPK nuclear retention and inhibits its activity towards H2B and EZH2.
• UHRF1 inhibits cytoplasmic AMPK activity, likely via nucleocytoplasmic shuttling.
• UHRF1 acts as a scaffold, recruiting PP2A phosphatase to dephosphorylate AMPK.
• Hepatic UHRF1 overexpression impacts glucose/lipid metabolism in wild-type mice but not AMPK-deficient mice.
• Adipose UHRF1 knockdown activates AMPK, reducing adipocyte size and lipogenesis.

Conclusions:

• UHRF1 is a novel suppressor of AMPK activity, functioning as a gatekeeper.
• UHRF1 plays critical roles in regulating cellular metabolism, particularly glucose and lipid homeostasis.
• Targeting UHRF1 may offer therapeutic strategies for metabolic disorders.