Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.BGT and MC were fellows of the FPI: Severo Ochoa CNIC program (SVP-2013–067639) and (BES-2017–079711) respectively. IN was funded by EFSD/Lilly grants (2017 and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012–600396), EFSD Rising Star award (2019), JDC-2018-Incorporación (MIN/JDC1802). T-L was a Juan de la Cierva fellow (JCI2011–11623). C.F has a Sara Borrell contract (CD19/00078). RJD is an Investigator of the Howard Hughes Medical Institute. This work was funded by the following grants to GS: funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n˚ ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17] _BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00 , EUIN201785875, Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación AECC AECC PROYE19047SABI and AECC: INVES20026LEIV to ML. MM was funded by ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 and JL-T by Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17. The study was additionally funded by MEIC grants to ML (MINECO-FEDER-SAF2015-74112-JIN) AT-L (MINECO-FEDERSAF2014-61233-JIN), RJD: Grant DK R01 DK107220 from the National Institutes of Health. AH: (SAF2015-65607-R). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015–0505).S

Hepatic p63 regulates steatosis via IKK beta/ER stress

p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKK beta activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKK beta and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKK beta silencing. Our findings indicate an unexpected role of the p63/IKK beta/ER stress pathway in lipid metabolism and liver disease.We deeply thank Dr Manuel Serrano (Spanish National Cancer Research Center, CNIO, Spain) for kindly providing p53 null mice and critically reading the article. This work has been supported by grants from Ministerio de Economia y Competitividad (C.D.: BFU2014-55,871; R.N.: BFU2015-70,664-R; M.M.M.: BFU2013-44229-R; A.C.: SAF2016-79381-R, FEDER/UE; GS: SAF2013-43506-R; M.L.M.-C.: SAF2014-54658-R; M.L.: SAF2015-71026-R; P.A.: SAF2015-64352-R; B.G.-T.: FPI Severo Ochoa CNIC program SVP-2013-067639), Xunta de Galicia (M.L.: 2015-CP079; R.N.: 2015-CP080 and PIE13/00024), Comunidad de Madrid (G.S.: S2010/BMD-2326); Fondo de Investigaciones Sanitarias (M.M.: PI10/01692), Fundacion SEEN (R.N.), GV-Departamento de Salud-2013111114 (to M.L.M.-C.), ISCIII: PIE14/00031 (to M.L.M.-C.), Junta Provincial de Bizkaia-AECC (to M.L.M.-C.), AECC (T.C.D.); Basque Department of Industry, Tourism and Trade (Etortek) (A.C.), the BBVA foundation (A.C.), Fundacion AstraZeneca (R.N.) Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. The participation of A.C. and A.Z.-L. as part of CIBERONC was co-funded with FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: A.C.: ERC StG-336343; R.N.: ERC StG-281408 and G.S.: ERC StG-260464.S