Editors' ChoicePhysiology

Taking Fatty Liver Disease Down a Notch

Sci. Signal.  27 Aug 2013:
Vol. 6, Issue 290, pp. ec201
DOI: 10.1126/scisignal.2004681

Nonalcoholic fatty liver disease, also known as hepatosteatosis or fatty liver, is an obesity-induced metabolic disease that causes liver inflammation and fibrosis and that can lead to death. Oddly, it is compounded by diabetes, despite the loss of insulin signaling that is normally required for fat synthesis. Pajvani et al. found that obesity-induced Notch signaling activates a transcriptional program that stabilizes mammalian target of rapamycin complex 1 (mTORC1) independently of insulin signaling. Hepatocytes from obese or high-fat diet (HFD)–fed mice had higher abundance of the cleaved Notch intracellular domain (NICD) and increased expression of Notch targets, such as Hey, and other transcription factors and their targets (notably the insulin signaling target Srebp1c and its targets) compared with hepatocytes from normal chow-fed mice. Mice lacking L-Rbpj (liver-specific recombination signal binding protein for immunoglobulin κ J region), a transcription factor that binds NICD, had decreased basal abundance of Acc1 (acetyl CoA carboxylase) and Fasn (fatty acid synthase), attenuated HFD-induced Hey expression, and decreased HFD-induced hepatic triglycerides and hepatosteatosis compared with wild-type mice. L-Rbpj–deficient mice also had increased insulin-induced Akt activation and decreased mTORC1 activity, suggesting that the usual mTORC1-mediated feedback inhibition of insulin signaling was attenuated by the loss of Notch signaling. Either inhibition of mTOR (through knockdown of Raptor or treatment with rapamycin) or liver-specific expression of a dominant-negative Notch1 receptor induced similar phenotypes to those seen in L-Rbpj–deficient mice. L-Rbpj–deficient mice showed decreased abundance of Raptor at the protein but not mRNA level, and treatment with a protein synthesis inhibitor, but not a proteasome inhibitor, prevented an increase in Raptor abundance induced by overexpression of constitutively active Notch1 receptor, indicating that Notch signaling stabilizes mTORC1 by inducing translation of RPTOR mRNA. The therapeutic potential of Notch signaling inhibitors may be complicated by toxicity and crosstalk complexity (see Czech). Nonetheless, the findings identify possible targets for treating fatty liver disease in obese diabetics.

U. B. Pajvani, L. Qiang, T. Kangsamaksin, J. Kitajewski, H. N. Ginsberg, D. Accili, Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat. Med. 19, 1054–1060 (2013). [PubMed]

M. P. Czech, Obesity Notches up fatty liver. Nat. Med. 19, 969–971 (2013). [PubMed]