Post Transcriptional Regulation of Lipogenesis

Obesity and insulin resistance are strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). The excess triglyceride that accumulates in hepatocytes is derived from multiple sources, one of which is de novo lipogenesis. Lipogenesis in liver is regulated by SREBP‐1c, a transcription factor that activates genes involved in fatty acid synthesis. The first committed enzyme in fatty acid synthesis, acetyl‐CoA carboxylase (ACC), is also regulated by phosphorylation/dephosphorylation, and protein polymerization. Previously, we showed that MIG12, a 22 kDa cytosolic protein, binds to ACC and lowers the threshold for citrate‐induced ACC activation. In vitro, recombinant MIG12 induced recombinant ACC polymerization and increased ACC activity by >50‐fold. In vivo, adenoviral overexpression of MIG12 induced ACC polymerization, increased fatty acid synthesis, resulting in triglyceride accumulation and fatty liver. A second protein, Spot14 (S14) shares significant homology with MIG12, is also highly expressed in liver and is regulated by SREBP‐1c. The mechanism for S14's ability to modulate lipogenesis has not been completely elucidated. In vitro biochemical studies and in vivo studies show that S14 can form a heterodimer with MIG12. Recombinant MIG12;S14 heterodimeric proteins also had no effect on ACC polymerization or activity and reduced overall flux through the fatty acid synthesis pathway, suggesting that S14 has an additional role in regulating fatty acid synthesis. Here, we further explore the interrelated molecular and physiological functions of lipogenic regulators in the regulation of lipogenesis. Support or Funding Information Foundation LeDucq Network Award NIH‐HL020948