Hepatic Stearoyl-CoA desaturase-1 deficiency-mediated activation of mTORC1- PGC-1\u03b1 axis regulates ER stress during high-carbohydrate feeding

Ahmed Aljohani,James M Ntambi,Mohammad Imran Khan,Sarah Lewis,Bonneville Abram,Hasan Mukhtar,Lucas O’ Neill,Deeba N Syed

doi:10.1038/s41598-019-52339-7

Abstract

Stearoyl CoA desaturase 1 (SCD1) is a key enzyme in lipogenesis as it catalyzes the synthesis of monounsaturated fatty acids (MUFAs), mainly oleate (18:1n9) and palmitoleate (16:1n7) from saturated fatty acids (SFA), stearate (18:0) and palmitate (16:0), respectively. Studies on SCD1 deficiency in mouse models demonstrated beneficial metabolic phenotypes such as reduced adiposity and improved glucose tolerance. Even though, SCD1 represents a potential target to resolve obesity related metabolic diseases; SCD1 deficiency causes endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). The induction of ER stress in response to SCD1 deficiency is governed by the cofactor, PGC-1α. However, the mechanism by which SCD1 deficiency increases PGC-1α and subsequently induces ER stress still remains elusive. The present study demonstrates that despite reduced lipogenesis, liver specific SCD1 deficiency activates the mechanistic target of rapamycin complex 1 (mTORC1) along with induction of PGC-1α and ER stress. Further, mTORC1 inhibition attenuates SCD1 deficiency-mediated induction of both PGC-1α and ER stress. Similar observations were seen by restoring endogenously synthesized oleate, but not palmitoleate, suggesting a clear mTORC1-mediated regulation of ER stress during SCD1 deficiency. Overall, our results suggest a model whereby maintaining adequate levels of hepatic oleate is required to suppress mTORC1-mediated ER stress. In addition, the activation of mTORC1 by SCD1 deficiency reveals an important function of fatty acids in regulating different cellular processes through mTORC1 signaling.

Highlights

Stearoyl CoA desaturase 1 (SCD1) is a key enzyme in lipogenesis catalyzing the rate limiting step in the synthesis of monounsaturated fatty acids (MUFA)
SCD1 deficiency prompted us to study the signaling pathways that govern the expression of lipogenic genes10,12. mechanistic target of rapamycin complex 1 (mTORC1) is one of the signaling pathways that have been shown to regulate the expression of lipogenic genes, including SCD1, mainly through promoting SREBP1c maturation and nuclear translocation[5,13]
We determined the effect of SCD1 deficiency and investigated the differential effects of endogenous MUFA supplementation on mTORC1 signaling pathway, which is a critical regulator of hepatic de novo lipogenesis

Summary

Introduction

Stearoyl CoA desaturase 1 (SCD1) is a key enzyme in lipogenesis catalyzing the rate limiting step in the synthesis of monounsaturated fatty acids (MUFA). We recently showed that induced expression of ER stress genes in response to SCD1 deficiency is mediated through peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)[11]. HCD feeding study revealed that SCD1 deficiency activates mTORC1 signaling pathway and uncouples active mTORC1 mediated lipogenesis. In response to SCD1 deficiency, active mTORC1 contributes to the induction of PGC1α mediated ER stress. Oleate mediated suppression of mTORC1 was observed in the liver of LKO mice fed triolein, but not tristearin, supplemented HCD. These findings indicate a pivotal role of hepatic oleate to suppress mTORC1 signaling and thereby mTORC1 mediated ER stress. This study provides valuable insight into the involvement of fatty acids in modulating cellular responses through mTORC1

Methods

Results

Conclusion