The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

Yael Aylon, Anat Gershoni, Ron Rotkopf, Inbal E. Biton, Ziv Porat, Anna P. Koh, Xiaochen Sun, Youngmin Lee, Maria Isabel Fiel, Yujin Hoshida, Scott L. Friedman, Randy L. Johnson, Moshe Oren

Research output: Contribution to journalArticle

37 Scopus citations

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 liverderived cells identified the transcription factor SREBP2, master regulator of cholesterol homeostasis. LATS2 downregulation caused SREBP activation and accumulation of excessive cholesterol. Likewise, mice harboring liverspecific 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 SREBPmediated 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.

Original languageEnglish (US)
Pages (from-to)786-797
Number of pages12
JournalGenes and Development
Volume30
Issue number7
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Keywords

  • Cholesterol
  • Fatty liver
  • Hippo
  • Lats
  • P53
  • YAP

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Aylon, Y., Gershoni, A., Rotkopf, R., Biton, I. E., Porat, Z., Koh, A. P., Sun, X., Lee, Y., Fiel, M. I., Hoshida, Y., Friedman, S. L., Johnson, R. L., & Oren, M. (2016). The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation. Genes and Development, 30(7), 786-797. https://doi.org/10.1101/gad.274167.115