Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function

Area of Science:

• Molecular Biology
• Genetics
• Metabolic Diseases

Background:

• SR proteins regulate RNA splicing in vitro.
• In vivo roles of SR proteins are largely unknown due to embryonic lethality from gene deletion.

Purpose of the Study:

• To investigate the in vivo function of SRSF3 (SR protein splicing factor 3) in hepatocytes.
• To elucidate the role of SRSF3 in liver development, architecture, and metabolic regulation.

Main Methods:

• Generation of SRSF3HKO mice with hepatocyte-specific Srsf3 deletion.
• Analysis of liver architecture, hepatocyte maturation, and metabolic parameters (glucose, lipids, cholesterol).
• Identification of splicing alterations in target genes using molecular techniques.

Main Results:

• SRSF3HKO mice exhibit disrupted hepatic architecture and growth retardation.
• Impaired hepatocyte maturation, reduced glycogen storage, hypoglycemia, increased insulin sensitivity, and decreased cholesterol synthesis were observed.
• Aberrant splicing of key metabolic regulators (Hnf1α, Ern1, Hmgcs1, Dhcr7, Scap) was identified.

Conclusions:

• SRSF3 is essential for the morphological and functional differentiation of hepatocytes in vivo.
• SRSF3 controls a genetic program vital for glucose and lipid metabolism.
• These findings have implications for human liver diseases and metabolic disorders.