Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD

MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis

The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH

Effect of sex and RYR1 gene mutation on the muscle proteomic profile and main physiological biomarkers in pigs at slaughter

Gender and RYR1 gene mutation might have an effect on the muscle metabolic characteristics and on the animal's stress at slaughter, which could influence the process of muscle-to-meat conversion. Forty-eight pigs were distributed in a design including two factors: sex (male/female) and RYR1 genotype (NN/Nn). At slaughter, physiological blood biomarkers and muscle proteome were analyzed and carcass and meat quality traits were registered. Females had higher serum levels of glucose, urea, C-reactive protein "CRP", Pig-MAP and glutation-peroxidase "GPx" and lower levels of lactate, showed faster muscle pH decline and higher meat exudation. RYR1 mutation increased serum creatinine, creatine kinase and CRP and decreased GPx. The proteomic study highlighted significant effects of gender and RYR1 genotype on proteins related to fibre composition, antioxidant defense and post mortem glycolytic pathway, which correlate to differences of meat quality. This study provides interesting information on muscle biomarkers of the ultimate meat quality that are modulated by the animal's individual susceptibility to stress at slaughter.info:eu-repo/semantics/acceptedVersio

Assessing and unraveling sarcopenia: role of body weight in muscle wasting

Tesis con mención internacional. Tesis doctoral por el sistema de compendio de publicacionesIn this PhD Thesis we have tried to increase the knowledge about the mechanisms underlying sarcopenia progression. The excess of weight is considered as a powerful risk factor for the onset of muscle wasting and is studied through two different perspectives. In the first part of our work we have evaluated the effect of overweight in an elderly population, which has allowed us to identify the cellular alterations produced in an early stage of obesity and its relevance in aging. Overweight in the elders induces cellular bioenergetics depletion, altering cellular quality control mechanisms and thus, skeletal muscle maintenance. In the second part of this work, we have analyzed the skeletal muscle alterations in leptin deficient mice, as a model of severe obesity. Role and function of mitochondrial metabolism has been identified as essential for the regulation of cellular metabolism, especially in proteostasis balance. This study provides new mechanistic insights on the functional relevance of obesity in muscle quality and, supports the potential use of melatonin as a therapeutic supplement for obesity and its role on muscle-related preservation. Based on our results, melatonin appears to be a potential treatment for obesity-related disorders due to its ability to restore energy requirements by both mitochondrial remodeling and fuel utilization. Melatonin probably mitigates musculoskeletal alterations due the implication of circadian rhythms in fuel harvesting and energy homeostasis allowing the regulation of quality control mechanisms. In summary, these studies evidence that the excess of weight induces a metabolic reprogramming leading to a cellular metabolic modulation. However, what we face is not so much the increase in fat as such but the resulted metabolic imbalance, which leads to the alteration of the cellular mechanisms and the skeletal muscle wasting. Finally, by using C2C12 satellite cells, we have studied if the most relevant mechanism previously found could be involved in skeletal muscle impairment due to a lack of differentiation response of satellite cells. We found that senescence reprograms energy metabolism leading to altered autophagy and p66SHC responses. Similarly, our work demonstrates that autophagy and p66SHC are disrupted during the differentiation of senescent C2C12 cells leading to muscle wasting due to its implication in cell fate. The ability to reprogram these cellular pathways is an ambitious task and a future challenge to treat not only sarcopenia but also muscle atrophy

The mystery of mitochondria-ER contact sites in physiology and pathology: A cancer perspective

Mitochondria-associated membranes (MAM), physical platforms that enable communication between mitochondria and the endoplasmic reticulum (ER), are enriched with many proteins and enzymes involved in several crucial cellular processes, such as calcium (Ca2+) homeostasis, lipid synthesis and trafficking, autophagy and reactive oxygen species (ROS) production. Accumulating studies indicate that tumor suppressors and oncogenes are present at these intimate contacts between mitochondria and the ER, where they influence Ca2+ flux between mitochondria and the ER or affect lipid homeostasis at MAM, consequently impacting cell metabolism and cell fate. Understanding these fundamental roles of mitochondria-ER contact sites as important domains for tumor suppressors and oncogenes can support the search for new and more precise anticancer therapies. In the present review, we summarize the current understanding of basic MAM biology, composition and function and discuss the possible role of MAM-resident oncogenes and tumor suppressors