TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.

Abstract

BACKGROUND/AIMS\nMolecular mechanisms underlying the different susceptibility of men and women to NAFLD are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects.\n\n\nMETHODS\nCo-expression in HEK293A\xa0cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using antisense oligonucleotide (ASO) in dietary NAFLD mice with genetic deficiency of pRb or its downstream effector E2F1 and in primary human hepatocytes.\n\n\nRESULTS\nT39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independent of pRb. In human primary hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men.\n\n\nCONCLUSIONS\nWe have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women.\n\n\nLAY SUMMARY\nIn females, TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and expression of a major genetic risk factor for nonalcoholic fatty liver disease. TTC39B is a potential therapeutic target for nonalcoholic fatty liver disease, especially in women.