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 β-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 (5’TOP) mRNAs which encode proteins of the translation machinery and ribosome biogenesis. We aimed to investigate the role played by LARP1 in β-cells in vivo. Here we show that LARP1 is the most expressed LARP in mouse islets and human β-cells, being 2-4-fold more abundant than LARP1B, a member of the family that also interacts with mTORC1. Interestingly, β-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 β-cells (β-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 β-Larp1KO male mice in body weight gain, glucose levels and glucose tolerance at 8, 14 and 44 weeks of age. Female β-Larp1KO mice also performed normally during the glucose tolerance test. We then challenged the β-Larp1KO mice with high fat (HFD) or high branched-chain amino acid (BCAA) diets. During the course of 8 weeks in HFD, β-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 β-Larp1KO mice at 16 weeks under BCAA diet. In conclusion, LARP1 is the most abundant LARP in mouse islets and human β-cells and it is upregulated in diabetic subjects. While the lack of LARP1 specifically in β-cells did not alter glucose homeostasis in basal conditions, long-term high branched-chain amino acid feeding could impair glucose tolerance.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Email to: ebernalm{at}med.miami.edu, Ernesto Bernal-Mizrachi, MD, PhD, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USA. Fax: +1 (305) 243 4039