Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1

被引：87

作者：

Gosis, Bridget S. ^{[1
]}

Wada, Shogo ^{[1
]}

Thorsheim, Chelsea ^{[1
]}

Li, Kristina ^{[1
]}

Jung, Sunhee ^{[2
]}

Rhoades, Joshua H. ^{[1
,3
,4
]}

Yang, Yifan ^{[1
]}

Brandimarto, Jeffrey ^{[1
]}

Li, Li ^{[1
]}

Uehara, Kahealani ^{[5
,6
]}

Jang, Cholsoon ^{[2
]}

Lanza, Matthew ^{[7
]}

Sanford, Nathan B. ^{[1
]}

Bornstein, Marc R. ^{[1
]}

Jeong, Sunhye ^{[1
]}

Titchenell, Paul M. ^{[5
,6
]}

Biddinger, Sudha B. ^{[8
]}

Arany, Zoltan ^{[1
]}

机构：

[1] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[2] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92717 USA

[3] Univ Penn, Perelman Sch Med, Inst Biomed Informat, Philadelphia, PA 19104 USA

[4] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA

[7] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA

[8] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

来源：

SCIENCE | 2022年 / 376卷 / 6590期

关键词：

HOGG-DUBE SYNDROME; TUMOR-SUPPRESSOR; MOUSE MODEL; TRANSCRIPTION FACTORS; MAMMALIAN TARGET; READ ALIGNMENT; X-RECEPTOR; COMPLEX; FIBROSIS; AKT;

D O I：

10.1126/science.abf8271

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.

引用

页码：264 / +

页数：63

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