Hippo pathway cooperates with ChREBP to regulate hepatic glucose utilization.

Area of Science:

• Molecular Biology
• Metabolic Regulation
• Cell Signaling

Background:

• The Hippo pathway is a key regulator of organ size and cell proliferation.
• Emerging evidence links the Hippo pathway to glucose metabolism, but mechanisms remain unclear.

Purpose of the Study:

• To elucidate the role of the Hippo pathway and its effector YAP in regulating hepatocyte glucose metabolism.
• To investigate the interaction between YAP and ChREBP in response to dietary conditions.

Main Methods:

• Investigated the interaction between YAP and ChREBP in mouse hepatocytes.
• Utilized high-carbohydrate diets and manipulated YAP activity (phosphorylation/downregulation).
• Analyzed the expression of target genes involved in glycolysis and lipogenesis (e.g., L-PK, ACC).

Main Results:

• Yes-associated protein (YAP) interacts with carbohydrate response element binding protein (ChREBP) in hepatocyte nuclei.
• High carbohydrate diets inactivate the Hippo pathway, promoting YAP-ChREBP complex formation.
• This complex upregulates glycolysis and lipogenesis by increasing L-PK and ACC expression.
• Inhibiting YAP activity counteracts these metabolic effects.

Conclusions:

• YAP acts as a nuclear co-factor for ChREBP in hepatocytes.
• The Hippo pathway negatively regulates hepatocyte glycolysis and lipogenesis by inhibiting YAP-ChREBP function.
• This finding provides a novel mechanistic link between Hippo signaling and metabolic control.