Tordjmann, T. | Search bioRxiv

bioRxiv2021

The hormone Fibroblast Growth Factor 19 stimulates water intake

Fibroblast growth factor 19 (FGF19) is a hormone with pleiotropic metabolic functions, leading to ongoing development of analogues for the treatment of metabolic disorders. On the other hand, FGF19 is overexpressed in a sub-group of hepatocellular carcinoma (HCC) patients and has oncogenic properties. It is therefore crucial to precisely define FGF19 effects, notably chronic exposure to elevated concentrations of the hormone. We used hydrodynamic gene transfer approach to generate a transgenic mouse model with long-term FGF19 hepatic overexpression. Here we describe a novel effect of FGF19, namely stimulation of water intake. This phenotype, lasting at least over a 6-month period, depends on signaling in the central nervous system and is independent of FGF21, although it mimics some of its features. We further show that HCC patients with high levels of circulating FGF19 have a reduced natremia, indicating dispogenic features. The present study provides evidence of a new activity for FGF19, which could be clinically relevant in the context of FGF19 overexpressing cancers and treatment of metabolic disorders by FGF19 analogues.

physiology↗

bioRxiv2021

Hepatocyte serine palmitoyl transferase 2 deficiency promotes liver C16:0-ceramide accumulation through sphingomyelin hydrolysis and leads to liver damage and dysfunction in mice

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell signalling pathways especially insulin signalling pathway leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic Cer synthesis on energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of Cer de novo synthesis, in hepatocytes. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, especially C16:0-Cer and C18:0-Cer associated with an increased neutral sphingomyelinase 2 expression, and a decreased sphingomyelin content in the liver. Sptlc2{Delta}Hep mice were protected against obesity induced by high fat diet. Bile acid (BA) hydrophobicity was drastically decreased in KO mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-muricholic acid in BA pool composition was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis worsening with age. Our data suggest a compensatory mechanism to regulate hepatic Cer content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the implication of hepatic sphingolipid modulation on BA metabolism and hepatic glucose production in an insulinin-dependent manner, which demonstrates the role of Cer in many metabolic functions still under-researched.

physiology↗