The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

• Published in: Genes & development Vol. 30; no. 7; pp. 786 - 797
• Main Authors: Aylon, Yael, Gershoni, Anat, Rotkopf, Ron, Biton, Inbal E., Porat, Ziv, Koh, Anna P., Sun, Xiaochen, Lee, Youngmin, Fiel, Maria-Isabel, Hoshida, Yujin, Friedman, Scott L., Johnson, Randy L., Oren, Moshe
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.04.2016
• Subjects: 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; Research Paper; 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; Lats; YAP; cholesterol; fatty liver; Hippo; p53
• DOI: 10.1101/gad.274167.115
• ISSN: 0890-9369; 1549-5477

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.