Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

Acute intermittent porphyria (AIP) is an inherited disorder of heme metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic -aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. Hemin represses ALAS1 and restores metabolic equilibrium. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. Chronically ill patients require repeated hemin infusions and develop secondary hemochromatosis and have a poorer quality of life. To decipher the mechanisms underlying recurrence in AIP patients, we studied the metabolic pathways altered by chronic hemin administration. A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to 5 human explanted livers. The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. We show that repeated hemin infusions trigger a high level heme oxygenase 1 (HO1) response, induce a pro-oxidative iron accumulation and a complex pattern of liver inflammation with macrophage infiltration. Conclusion: chronically heme-treated AIP patients may present with symptoms of an inflammatory disease responsible for an adaptive HO1 induction that could deplete the free heme pool inducing ALAS1. Hemin remains the most effective treatment but should be restricted to patients with severe forms of AIP to prevent chronic damage

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

[Background] Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. [Objective] The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. [Methods] A follow‐up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs−/− mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. [Results] The introduction of hemin into the pharmacopeia has coincided with a 4.4‐fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. [Conclusion] Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti‐inflammatory therapies should be considered in patients with recurrent AIP.LG, JCD, PH, ES and AKA were funded for attending meeting related to ongoing clinical trial by Alnylam Pharmaceuticals.Peer reviewe

Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation

Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-α (TNF-α)], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response

Oligocene and miocene global spatial trends of shallow-marine carbonate architecture

The present study provides the baseline status of the spatial distribution of carbonate platforms for the Oligo-Miocene interval. The resulting global trend quantitatively shows the decreasing growth potential of shallow-marine carbonates toward higher paleolatitudes. Such a global trend provides a geological context and external constraints for local and regional interpretations of specific case studies. Furthermore, the direct relationship between carbonate accumulations and paleoclimatic regions shows that, using such a qualitative and quantitative data set for calibration, paleoceanographic models could be utilized for the prediction of the global distribution of carbonate stratigraphic architecture