Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin ...exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
Methionine adenosyltransferase 1A (MAT1A) and glycine N‐methyltransferase (GNMT) are the primary genes involved in hepatic S‐adenosylmethionine (SAMe) synthesis and degradation, respectively. Mat1a ...ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. Gnmt‐deficient mice, despite showing a large increase in hepatic SAMe, also develop steatosis. We hypothesized that as an adaptive response to hepatic SAMe accumulation, phosphatidylcholine (PC) synthesis by way of the phosphatidylethanolamine (PE) N‐methyltransferase (PEMT) pathway is stimulated in Gnmt−/− mice. We also propose that the excess PC thus generated is catabolized, leading to TG synthesis and steatosis by way of diglyceride (DG) generation. We observed that Gnmt−/− mice present with normal hepatic lipogenesis and increased TG release. We also observed that the flux from PE to PC is stimulated in the liver of Gnmt−/− mice and that this results in a reduction in PE content and a marked increase in DG and TG. Conversely, reduction of hepatic SAMe following the administration of a methionine‐deficient diet reverted the flux from PE to PC of Gnmt−/− mice to that of wildtype animals and normalized DG and TG content preventing the development of steatosis. Gnmt−/− mice with an additional deletion of perilipin2, the predominant lipid droplet protein, maintain high SAMe levels, with a concurrent increased flux from PE to PC, but do not develop liver steatosis. Conclusion: These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration. (Hepatology 2013;58:1296–1305)
Very low‐density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In nonalcoholic fatty liver ...disease (NAFLD), VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S‐adenosylmethionine (SAMe) synthesis and MAT I and III are the products of the MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD, but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3‐month‐old MAT1A‐knockout mice (3‐KO), with no signs of liver injury, and in 8‐month‐old MAT1A‐knockout mice (8‐KO), harboring nonalcoholic steatohepatitis. In 3‐KO mouse liver, there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores, TG secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N‐methyltransferase. MAT1A deletion also increased VLDL– apolipoprotein B secretion, leading to small, lipid‐poor VLDL particles. Administration of SAMe to 3‐KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded protein response was activated in 8‐KO mouse liver, in which TG accumulated and the phosphatidylcholine‐to‐phosphatidylethanolamine ratio was reduced in the endoplasmic reticulum, whereas secretion of TG and apolipoprotein B in VLDL was increased and the VLDL physical characteristics resembled that in 3‐KO mice. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in low‐density lipoprotein subclasses and decrease in high‐density lipoprotein subclasses. Conclusion:
MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice. Impaired VLDL synthesis, mainly due to SAMe deficiency, contributes to NAFLD development in MAT1A‐KO mice. (HEPATOLOGY 2011
Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β double ...heterozygous (DH) to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro‐thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria‐rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ‐specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
Introduction
Clostridioides difficile
infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a ...growing medical problem. Data from real-life studies and one open label randomised clinical trial (RCT) suggest that secondary prophylaxis with oral vancomycin (SPV) during subsequent courses of systemic antibiotics is a promising approach for reducing the risk of CDI recurrence. Our aim is to confirm the role of SPV through a double-blind RCT.
Methods and analysis
We will perform a phase III, multicentre, placebo-controlled RCT (PREVAN trial) in a 2:1 ratio in favour of SPV (experimental treatment), in four tertiary care hospitals in Spain. Adult patients (≥18 years) with a previous history of CDI in the previous 180 days and with requirement for hospitalisation and systemic antibiotic therapy will be randomly allocated to receive either 125 mg of oral vancomycin or placebo every 6 hours for 10 days. Patients will be followed for 60 days after the end of treatment to verify a reduction in the rate of CDI recurrence in the experimental group. We assume a recurrence rate of 5% in the experimental group versus 25% in the placebo group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 104 subjects will be required in total (68 assigned to the SPV group and 34 to the placebo group).
Ethics and dissemination
Ethical approval has been obtained from the Ethic Committee for Research with medicinal products of the University Hospital ‘12 de Octubre’ (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), which is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.
Trial registration number
NCT05320068
.
Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and ...carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil.
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•Liver-X nuclear receptor-β signaling enhances the proliferation of DFTD cells•DFTD cells depend on carbohydrate metabolism to proliferate•Maintaining cholesterol homeostasis is essential for the proliferation of DFTD cells•Atorvastatin constitutes a feasible treatment against DFTD-infected animals
Devil facial tumor disease (DFTD) threatens the Tasmanian devil with extinction. Ikonomopoulou et al. investigate how the energy metabolism of DFTD cells drives tumor growth. Using in vitro and in vivo models, they characterize the impact of cholesterol homeostasis imbalance in the integrity and proliferation of DFTD cells and tumors.
Very-low-density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In non-alcoholic fatty-liver ...disease (NAFLD) VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S-adenosylmethionine (SAMe) synthesis and MAT I and III are the products of MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3-month-old MAT1A-knockout mice (3-KO), with no signs of liver injury, and in 8-month-old MAT1A-knockout mice (8-KO), harbouring non-alcoholic steatohepatitis (NASH). In 3-KO mice liver there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores and secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N-methyltransferase. MAT1A deletion also increased VLDL-apoB secretion leading to small, lipid poor VLDL particles. Administration of SAMe to 3-KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded-protein-response was activated in 8-KO mice liver, in which TG-accumulated and the phosphatidylcholine to phosphatidylethanolamine ratio reduced in the ER, whereas the secretion of TG and apoB in VLDL increased and the VLDL physical characteristics resembled that in 3-KO. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in LDL-subclasses and decrease in HDL-subclasses.
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