The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

We are what we eat: The role of lipids in metabolic diseases.

Lipids play a fundamental role, both structurally and functionally, for the correct functioning of the organism. In the last two decades, they have evolved from molecules involved only in energy storage to compounds that play an important role as components of cell membranes and signaling molecules that regulate cell homeostasis. For this reason, their interest as compounds involved in human health has been gaining weight. Indeed, lipids derived from dietary sources and endogenous biosynthesis are relevant for the pathophysiology of numerous diseases. There exist pathological conditions that are characterized by alterations in lipid metabolism. This is particularly true for metabolic diseases, such as liver steatosis, type 2 diabetes, cancer and cardiovascular diseases. The main issue to be considered is lipid homeostasis. A precise control of fat homeostasis is required for a correct regulation of metabolic pathways and safe and efficient energy storage in adipocytes. When this fails, a deregulation occurs in the maintenance of systemic metabolism. This happens because an increased concentrations of lipids impair cellular homeostasis and disrupt tissue function, giving rise to lipotoxicity. Fat accumulation results in many alterations in the physiology of the affected organs, mainly in metabolic tissues. These alterations include the activation of oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, increased inflammation, accumulation of bioactive molecules and modification of gene expression. In this chapter, we review the main metabolic diseases in which alterations in lipid homeostasis are involved and discuss their pathogenic mechanisms.

Contribution of Liver and Pancreatic Islet Crosstalk to ß-Cell Function/Dysfunction in the Presence of Fatty Liver.

Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic ß-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic ß-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic ß-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic ß-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic ß-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.

NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function.

LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist-ONO-8130-negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.

Healthy Habits in Firefighters: Assessment in Shift Days Versus Days Off.

OBJECTIVE: The aim of this study was to compare dietary habits, sleep habits, and injury incidence between shift days and days off among Spanish firefighters. METHODS: 24-Hour dietary recalls, and sleep and injury questionnaires on both days were collected from 28 Sevillian professional firefighter, as well as anthropometric measurements and a physical activity questionnaire. RESULTS: Firefighters consumed 433 more kilocalories (P < 0.001), 2.4% and 3.1% more kilocalories from fat and monounsaturated fatty acids, respectively (P < 0.05), had 3.7 times greater chance of being injured and slept 2 hours and 18 minutes less (P < 0.001) in their shift days. Higher body fat percentages were found in older and less active firefighters. CONCLUSIONS: Shift work appears to influence their dietary habits, injury incidence, and sleep habits, so measures to alleviate the consequences of shift work in firefighters should be taken.

Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr-/-.Leiden mice without attenuation of steatohepatitis.

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr-/-. Leiden mice. In female Ldlr-/-.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression.