Autophagy inhibition by biotin elicits endoplasmic reticulum stress to differentially regulate adipocyte lipid and protein synthesis
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Biotin is an indispensable adipogenic agent, and its ability to coordinate carbohydrate, lipid, and amino acid metabolism sensitizes insulin signaling in adipocytes. This enables the organism to adapt and survive under nutrient stress by synthesis and storage of lipids. Biotin deficiency mimics insulin resistance with alterations in cellular intermediary metabolism. Though the mechanism of lipogenesis is well established across cell types, considering its predisposition to accumulate only lipids, it is necessary to elucidate the mechanism that minimizes the effects of biotin on adipocyte protein synthesis. In order to determine the differential metabolic phenotype by biotin, the primary cultures of adipocytes were induced to differentiate in the presence and absence of excess biotin. Serum pre-incubated with avidin was used to limit biotin availability in cultured cells. Biotin restricts cellular signaling associated with protein synthesis without altering total protein content. The decline in autophagy elicits endoplasmic reticulum stress to inhibit protein synthesis by eIF2α phosphorylation possibly via accumulation of misfolded/long-lived proteins. Furthermore, the compensatory increase in Unc51 like autophagy activating kinase 1 possibly competes with eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6kinase phosphorylation by mechanistic targets of rapamycin complex 1 to uncouple its effect on protein synthesis. In conclusion, autophagy inhibition by biotin uncouples protein synthesis to promote lipogenesis by eliciting endoplasmic reticulum stress and differential phosphorylation of mechanistic targets of rapamycin complex 1 substrates.
KeywordsBiotin Autophagy ER stress mTORC1 Amino acids Protein synthesis
We would also like to acknowledge DBT-BUILDER program (BT/PR12153/INF/22/200/2014) for providing HPLC instrumentation and Dr. S. Meenakshisundaram’s research group for their assistance with HPLC analysis. The authors SRS and ARS acknowledge ICMR, Government of India for Senior Research Fellowship award.
This study was supported in part by grants-in-aid for research from DST-SERB (SR/S0/HS/0051/2012 and EMR/2016/003276).
Compliance with ethical standards
The protocols for animal maintenance and usage were approved by the Institutional Animal Ethics Committee.
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