Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice.

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Roles of Ceramides in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity epidemic. Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity. We review here the evidence showing the role of ceramides in non-alcoholic fatty liver disease and the mechanisms underlying their effects.

Dihydroceramides: their emerging physiological roles and functions in cancer and metabolic diseases.

Dihydroceramides (DhCers) are a type of sphingolipids that for a long time were regarded as biologically inactive. They are metabolic intermediates of the de novo sphingolipid synthesis pathway, and are converted into ceramides (Cers) with the addition of a double bond. Ceramides are abundant in tissues and have well-established biological functions. On the contrary, dihydroceramides are less prevalent, and despite their hitherto characterization as inert lipids, studies of the past decade began to unravel their implication in various biological processes distinct from those involving ceramides. These processes include cellular stress responses and autophagy, cell growth, pro-death or pro-survival pathways, hypoxia, and immune responses. In addition, their plasma concentration has been related to metabolic diseases and shown as a long-term predictor of type 2 diabetes onset. They are thus important players and potential biomarkers in pathologies ranging from diabetes to cancer and neurodegenerative diseases. The purpose of this mini-review is to highlight the emergence of dihydroceramides as a new class of bioactive sphingolipids by reporting recent advances on their biological characterization and pathological implications, focusing on cancer and metabolic diseases.

Dihydroceramides in Triglyceride-Enriched VLDL Are Associated with Nonalcoholic Fatty Liver Disease Severity in Type 2 Diabetes.

Plasma dihydroceramides are predictors of type 2 diabetes and related to metabolic dysfunctions, but the underlying mechanisms are not characterized. We compare the relationships between plasma dihydroceramides and biochemical and hepatic parameters in two cohorts of diabetic patients. Hepatic steatosis, steatohepatitis, and fibrosis are assessed by their plasma biomarkers. Plasma lipoprotein sphingolipids are studied in a sub-group of diabetic patients. Liver biopsies from subjects with suspected non-alcoholic fatty liver disease are analyzed for sphingolipid synthesis enzyme expression. Dihydroceramides, contained in triglyceride-rich very-low-density lipoprotein (VLDL), are associated with steatosis and steatohepatitis. Expression of sphingolipid synthesis enzymes is correlated with histological steatosis and inflammation grades. In conclusion, association of plasma dihydroceramides with nonalcoholic fatty liver might explain their predictive character for type 2 diabetes. Our results suggest a relationship between hepatic sphingolipid metabolism and steatohepatitis and an involvement of dihydroceramides in the synthesis/secretion of triglyceride-rich VLDL, a hallmark of NAFLD and type 2 diabetes dyslipidemia.

[ER stress and NAFLD]. / Stress du réticulum endoplasmique et stéatopathies métaboliques.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent pathology associated with obesity. It encompasses a spectrum of hepatic disorders ranging from steatosis to non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress has been widely involved to drive in NAFLD progression through the activation of the unfolded protein response (UPR). While transient UPR activation can boost hepatic ER functions, its continuous activation upon a chronic ER stress contributes to lipid accumulation, inflammation and hepatocyte death, which are determinant factors for the progression to more severe stages. The aim of this review is to describe the mechanisms through which the UPR can take part in the transition from a healthy to a diseased liver and to report on possible ways of pharmacological manipulation against these pathological mechanisms.

TITLE: Stress du réticulum endoplasmique et stéatopathies métaboliques. ABSTRACT: Les stéatopathies métaboliques sont des pathologies en pleine expansion car très associées à l'obésité. Elles englobent un éventail de troubles hépatiques allant de la stéatose à la stéatohépatite non alcoolique (NASH) pouvant conduire à la cirrhose et au carcinome hépatocellulaire (CHC). Le stress du réticulum endoplasmique (RE), à travers l'activation de la voie UPR (Unfolded Protein Response), a été largement impliqué dans le développement et la progression de ces maladies métaboliques hépatiques. Alors que l'activation transitoire de la voie UPR fait partie intégrante de la physiologie hépatique, son activation chronique contribue à la stimulation de voies métaboliques et cellulaires (synthèse des lipides, inflammation, apoptose) qui sont déterminantes dans la progression vers des stades sévères. Le but de cette revue est de décrire comment la voie UPR participe au passage d'un foie sain à un foie malade au cours de l'obésité et d'analyser les perspectives thérapeutiques liées à la manipulation pharmacologique de cette voie.