title: The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation.
abstract: The Hippo signaling pathway is a major regulator of organ size. In the liver, Hippo pathway deregulation promotes hyperplasia and hepatocellular carcinoma primarily through hyperactivation of its downstream effector, YAP. The LATS2 tumor suppressor is a core member of the Hippo pathway. A screen for LATS2-interacting proteins in liver-derived cells identified the transcription factor SREBP2, master regulator of cholesterol homeostasis. LATS2 down-regulation caused SREBP activation and accumulation of excessive cholesterol. Likewise, mice harboring liver-specific Lats2 conditional knockout (Lats2-CKO) displayed constitutive SREBP activation and overexpressed SREBP target genes and developed spontaneous fatty liver disease. Interestingly, the impact of LATS2 depletion on SREBP-mediated transcription was clearly distinct from that of YAP overexpression. When challenged with excess dietary cholesterol, Lats2-CKO mice manifested more severe liver damage than wild-type mice. Surprisingly, apoptosis, inflammation, and fibrosis were actually attenuated relative to wild-type mice, in association with impaired p53 activation. Subsequently, Lats2-CKO mice failed to recover effectively from cholesterol-induced damage upon return to a normal diet. Additionally, decreased LATS2 mRNA in association with increased SREBP target gene expression was observed in a subset of human nonalcoholic fatty liver disease cases. Together, these findings further highlight the tight links between tumor suppressors and metabolic homeostasis.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Yael
authors.initials: Y
authors.lastname: Aylon
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Anat
authors.initials: A
authors.lastname: Gershoni
authors.affiliation: Bioinformatics Unit, Faculty of Biological Services, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Ron
authors.initials: R
authors.lastname: Rotkopf
authors.affiliation: Department of Veterinary Resources, Faculty of Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Inbal E
authors.initials: IE
authors.lastname: Biton
authors.affiliation: Flow Cytometry Unit, Biological Services Department, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Anna P
authors.initials: AP
authors.lastname: Koh
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Sun
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
mesh_terms: D000818:Animals; D002791:Cholesterol, Dietary / Q000494:pharmacology; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D056945:Hep G2 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D018345:Mice, Knockout; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002791:Cholesterol, Dietary; D051782:Sterol Regulatory Element Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo; Lats; YAP; cholesterol; fatty liver; p53