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Genes Dev. 2016 Apr 1;30(7):786-97. doi: 10.1101/gad.274167.115. Epub 2016 Mar 24.

The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation.

Author information

1
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
2
Bioinformatics Unit, Faculty of Biological Services, The Weizmann Institute of Science, Rehovot 76100, Israel;
3
Department of Veterinary Resources, Faculty of Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
4
Flow Cytometry Unit, Biological Services Department, The Weizmann Institute of Science, Rehovot 76100, Israel;
5
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;
6
Department of Biochemistry and Molecular Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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.

KEYWORDS:

Hippo; Lats; YAP; cholesterol; fatty liver; p53

PMID:
27013235
PMCID:
PMC4826395
DOI:
10.1101/gad.274167.115
[Indexed for MEDLINE]
Free PMC Article

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