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Sci Rep. 2019 Oct 31;9(1):15761. doi: 10.1038/s41598-019-52339-7.

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

Author information

1
School of Medicine and Public Health, Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, 53706, USA.
2
King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, 11426, Saudi Arabia.
3
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 80203, Saudi Arabia.
4
Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, USA.
5
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
6
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA. james.ntambi@wisc.edu.
7
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 53706, USA. james.ntambi@wisc.edu.

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.

PMID:
31673045
DOI:
10.1038/s41598-019-52339-7
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