Role of TTC39B in Mediating NAFLD in Insulin-Resistant States

Non-alcoholic fatty liver disease (NAFLD) is very common in diabetes and insulin resistance and one feature is increased de novo lipogenesis (DNL). However, the mechanism for upregulated hepatic DNL is not well-understood. Deficiency in the scaffolding protein TTC39B results in protection from NAFLD in mice, associated with decreased hepatic lipogenic gene expression. TTC39B regulates hepatic lipogenic gene expression by interacting with and promoting the degradation of RB1. TTC39B also interacts with 14-3-3γ, which may sequester from the nucleus. Based on these observations, the PI hypothesizes that insulin resistance activates a phosphatase that releases TTC39B from 14-3-3γ binding, allowing TTC39B to enter the nucleus to degrade RB1, resulting in lipogenic gene expression. Aim 1 will use hepatic RB1-deficient mice to determine its contribution to hepatic lipogenic gene expression and NAFLD pathogenesis in vivo. RNA-Sequencing and ATAC-Sequencing analysis will be used to identify promoter and enhancer motifs that are affected in the TTC39B/RB1-dependent pathway. Aim 2 will use unbiased approaches to identify how TTC39B’s interaction with kinases and phosphatases change as insulin resistance and NAFLD develops. This study has the potential to identify a novel pathway that explains the upregulated DNL in insulin resistant individuals, and inform the development of new therapies to treat