Proto-oncoprotein Zbtb7c and SIRT1 repression: implications in high-fat diet-induced and age-dependent obesity

Abstract

Metabolic disease: SIRT1 gene, a potential therapeutic target Targeting a regulatory DNA sequence linked to the repression of a critical enzyme during metabolic diseases could prove valuable for future therapies. The SIRT1 enzyme is involved in metabolic processes and stress resistance, and its dysregulation is linked to obesity and diabetes development. SIRT1 expression also decreases with aging and stress, but the precise regulation mechanisms are unclear. In experiments on aging mice and mice fed a high-fat diet, Man-Wook Hur at Yonsei University in Seoul, South Korea, and co-workers demonstrated that SIRT1 expression is repressed by a protein called Zbtb7c, which is highly expressed in fat and liver tissues. Aging mice without the Zbtb7c-encoding gene had less fatty tissue than controls. Zbtb7c represses the SIRT1 gene by interacting with protein p53. A sequence critical to this repression mechanism may provide a therapeutic target. Zbtb7c is a proto-oncoprotein that controls the cell cycle and glucose, glutamate, and lipid metabolism. Zbtb7c expression is increased in the liver and white adipose tissues of aging or high-fat diet-fed mice. Knockout or knockdown of Zbtb7c gene expression inhibits the adipocyte differentiation of 3T3-L1 cells and decreases adipose tissue mass in aging mice. We found that Zbtb7c was a potent transcriptional repressor of SIRT1 and that SIRT1 was derepressed in various tissues of Zbtb7c-KO mice. Mechanistically, Zbtb7c interacted with p53 and bound to the proximal promoter p53RE1 and p53RE2 to repress the SIRT1 gene, in which p53RE2 was particularly critical. Zbtb7c induced p53 to interact with the corepressor mSin3A-HADC1 complex at p53RE. By repressing the SIRT1 gene, Zbtb7c increased the acetylation of Pgc-1 alpha and Ppar gamma, which resulted in repression or activation of Pgc-1 alpha or Ppar gamma target genes involved in lipid metabolism. Our study provides a molecular target that can overexpress SIRT1 protein in the liver, pancreas, and adipose tissues, which can be beneficial in the treatment of diabetes, obesity, longevity, etc.