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bioRxiv · 10.1101/2020.09.03.281832

Is there a role for the RNA-binding protein LARP1 in β-cells?

Werneck de Castro, J. P.·Pecanha, F. L. M.·Silvestre, D. H.·Bernal-Mizrachi, E.
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Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is a cellular rheostat linking nutrient availability and growth factor to cellular protein translation. In pancreatic insulin secreting {beta}-cells, mTORC1 deficiency or chronic hyperactivation leads to diabetes. mTORC1 complexes with La-related protein 1 (LARP1) to specifically regulate the expression of 5 terminal oligopyrimidine tract (5TOP) mRNAs which encode proteins of the translation machinery and ribosome biogenesis. We aimed to investigate the role played by LARP1 in {beta}-cells in vivo. Here we show that LARP1 is the most expressed LARP in mouse islets and human {beta}-cells, being 2-4-fold more abundant than LARP1B, a member of the family that also interacts with mTORC1. Interestingly, {beta}-cells from diabetic patients have higher LARP1 and LARP1B expression suggesting greater protein translation. These studies led us to generate a conditional LARP1 knockout mouse in {beta}-cells ({beta}-Larp1KO mice). These mice exhibit normal levels of all LARP family members including Larp1B, Larp4, Larp6 and Larp7. We did not observe any difference between control and {beta}-Larp1KO male mice in body weight gain, glucose levels and glucose tolerance at 8, 14 and 44 weeks of age. Female {beta}-Larp1KO mice also performed normally during the glucose tolerance test. We then challenged the {beta}-Larp1KO mice with high fat (HFD) or high branched-chain amino acid (BCAA) diets. During the course of 8 weeks in HFD, {beta}-Larp1KO and control mice had similar weight gain and did not show alterations in glucose homeostasis compared to control littermates. BCAA did not impair glucose metabolism up to 8 weeks of diet challenge. However, glucose tolerance was slightly impaired in the {beta}-Larp1KO mice at 16 weeks under BCAA diet. In conclusion, LARP1 is the most abundant LARP in mouse islets and human {beta}-cells and it is upregulated in diabetic subjects. While the lack of LARP1 specifically in {beta}-cells did not alter glucose homeostasis in basal conditions, long-term high branched-chain amino acid feeding could impair glucose tolerance.

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Werneck de Castro, J. P., Pecanha, F. L. M., Silvestre, D. H., Bernal-Mizrachi, E.. 2020-09-03. Is there a role for the RNA-binding protein LARP1 in β-cells?. https://doi.org/10.1101/2020.09.03.281832

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