Apolipoprotein A-IV Reduces Hepatic Gluconeogenesis through the Nuclear Receptor NR1D1 [Signal Transduction]

December 5th, 2013 by Li, X., Xu, M., Wang, F., Kohan, A. B., Haas, M. K., Yang, Q., Lou, D., Obici, S., Davidson, W. S., Tso, P.

We recently showed that apoA-IV improves glucose homeostasis by enhancing pancreatic insulin secretion in the presence of elevated level of glucose. We therefore examined whether apoA-IV also regulates glucose metabolism through the suppression of hepatic gluconeogenesis. The ability of apoA-IV to lower gluconeogenic gene expression and glucose production was measured in apoA-IV-/- and wild-type mice, and primary mouse hepatocytes. The transcriptional regulation of G6Pase and PEPCK by apoA-IV was determined by the luciferase activity assay. Using bacterial two-hybrid library screening, NR1D1 was identified as a putative apoA-IV-binding protein. The co-localization and interaction between apoA-IV and NR1D1 were confirmed by immunofluorescence, in situ Proximity Ligation Assay and co-immunopricipitation. Enhanced recruitment of NR1D1 and activity by apoA-IV to G6Pase promoter was verified with ChIP and luciferase assay. Down-regulation of apoA-IV on gluconeogenic genes is mediated through NR1D1 as illustrated in cells with NR1D1 knockdown by siRNA. We find that apoA-IV: 1) suppresses the expression of PEPCK and G6Pase in hepatocytes; 2) decreases hepatic glucose production; 3) binds and activates nuclear receptor NR1D1 and stimulates NR1D1 expression; and 4) in cells lacking NR1D1, fails to inhibit PEPCK and G6Pase gene expression; 5) higher hepatic glucose production and higher gluconeogenic gene expression in apoA-IV-/- mice. We conclude that apoA-IV inhibits hepatic gluconeogenesis by decreasing G6Pase and PEPCK gene expression through NR1D1. This novel regulatory pathway connects an influx of energy as fat from the gut (and subsequent apoA-IV secretion) with inhibition of hepatic glucose production.