The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol, Dietary / pharmacology
  • Fatty Liver / enzymology*
  • Fatty Liver / genetics
  • Gene Deletion
  • Gene Expression Regulation / genetics
  • Hep G2 Cells
  • Homeostasis / genetics
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Mice, Knockout
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cholesterol, Dietary
  • Sterol Regulatory Element Binding Protein 2
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • LATS2 protein, human
  • LATS2 protein, mouse
  • Protein-Serine-Threonine Kinases