A functional interaction between Hippo-YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

Area of Science:

• Cell Biology
• Metabolic Disease Research
• Molecular Biology

Background:

• The Hippo pathway is a key regulator of organ size and cell growth.
• Its role in regulating cellular metabolism, particularly in hepatocytes, remains largely unexplored.
• Understanding metabolic regulation is crucial for addressing diseases like diabetes and hyperlipidemia.

Purpose of the Study:

• To investigate the role of the Hippo pathway, specifically Yes-associated protein (YAP), in regulating hepatocyte metabolism.
• To determine if YAP interacts with key metabolic regulators like sterol regulatory element binding proteins (SREBPs).
• To explore the therapeutic potential of modulating the Hippo pathway in metabolic diseases.

Main Methods:

• Investigated the interaction between YAP and SREBPs (SREBP-1c and SREBP-2) in hepatocyte nuclei.
• Analyzed the effect of YAP-SREBP interaction on the transcription of genes involved in lipogenesis and cholesterol synthesis (FAS and HMGCR).
• Utilized diet-induced diabetic mouse models with Lats1 overexpression and YAP knockdown to assess the impact on hepatic steatosis and hyperlipidemia.

Main Results:

• YAP directly interacts with SREBP-1c and SREBP-2 at the promoters of FAS and HMGCR, stimulating their transcription.
• This interaction promotes hepatocyte lipogenesis and cholesterol synthesis.
• In diet-induced diabetic mice, inhibiting the YAP-SREBP interaction (via Lats1 overexpression or YAP knockdown) protected against hepatic steatosis and hyperlipidemia.

Conclusions:

• YAP acts as a nuclear co-factor for SREBPs, linking the Hippo pathway to lipid and cholesterol metabolism.
• The Hippo pathway negatively regulates hepatocyte lipogenesis by inhibiting the function of YAP-SREBP complexes.
• Targeting the YAP-SREBP interaction presents a potential therapeutic strategy for managing metabolic disorders like hepatic steatosis and hyperlipidemia.