Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation.

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.

Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.

Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.

Noise in the operating room during induction of anesthesia: impact of a quality improvement initiative.

PURPOSE: Noise in the operating room (OR) is common and associated with negative effects on anesthesiologists, surgeons, and patient outcomes. Induction of anesthesia is among the loudest perioperative periods. Despite its critical nature, there is little data on noise levels during induction, associated patient and anesthesiologist satisfaction, and the effects of noise reduction strategies. METHODS: We conducted a two-part prospective interventional quality improvement project on the care of adult patients receiving general anesthesia for elective noncardiac surgery. For part A, we measured average and peak noise (dB[A]) levels during anesthesia induction in N = 100 cases and administered a satisfaction questionnaire to anesthesiologists. We then applied a multidisciplinary educational program to OR personnel on active noise reduction strategies and subsequently collected data during N = 109 cases in a post-intervention phase. For part B, we administered satisfaction questionnaires to N = 100 patients pre- vs postintervention, respectively. RESULTS: Median [interquartile range] noise levels throughout induction were 66.0 [62.5-68.6] dB(A) preintervention vs 63.5 [60.1-65.4] dB[A] post-intervention (Hodges-Lehmann estimator of the difference, - 2.7 dB[A]; 95% confidence interval [CI], - 4.0 to - 1.5; P < 0.001). Peak noise levels during induction were 87.3 [84.0-90.5] dB(A) preintervention and 86.2 [81.8-89.3] dB(A) postintervention (Hodges-Lehmann estimator of the difference, - 1.8 dB[A]; 95% CI, - 3.3 to - 0.3; P = 0.02). Noise-related anesthesiologist satisfaction postintervention was significantly improved in multiple domains, including assessment of noise having distracted anesthesiologists. Patient satisfaction was high pre-intervention and did not significantly improve further. CONCLUSION: In this quality improvement project, average noise levels during induction of anesthesia, anesthesiologist satisfaction, and anesthesiologists' perceived ability to perform were improved following a multidisciplinary educational program on noise reduction in the OR. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04204785); registered 19 December 2019.

RéSUMé: OBJECTIF: Le bruit en salle d'opération (SOP) est fréquent et associé à des effets négatifs sur les anesthésiologistes, les chirurgiens et les issues des patients. L'induction de l'anesthésie est l'une des périodes périopératoires les plus bruyantes. Malgré sa nature critique, il existe peu de données sur les niveaux sonores pendant l'induction, la satisfaction des patients et des anesthésiologistes qui y est reliée, et les effets des stratégies de réduction du bruit. MéTHODE: Nous avons mené un projet prospectif et interventionnel, en deux parties, d'amélioration de la qualité sur les soins aux patients adultes recevant une anesthésie générale pour une chirurgie non cardiaque non urgente. Dans le cadre de la première partie A, nous avons mesuré les niveaux de bruit moyen et maximaux (dB[A]) pendant l'induction de l'anesthésie dans n = 100 cas et administré un questionnaire de satisfaction aux anesthésiologistes. Nous avons ensuite appliqué un programme de formation multidisciplinaire au personnel de la salle d'opération sur les stratégies de réduction active du bruit et avons ensuite recueilli des données pour n = 109 cas dans une phase post-intervention. Pour la deuxième partie B, nous avons administré des questionnaires de satisfaction à n = 100 patients pré- vs post-intervention, respectivement. RéSULTATS: Les niveaux de bruit médians [écart interquartile] tout au long de l'induction étaient de 66,0 [62,5­68,6] dB(A) avant l'intervention vs 63,5 [60,1­65,4] dB[A] après l'intervention (estimateur de Hodges-Lehmann, − 2,7 dB[A]; intervalle de confiance [IC] 95 %, − 4,0 à − 1,5; P < 0,001). Les niveaux maximaux de bruit pendant l'induction étaient de 87,3 [84,0­90,5] dB(A) avant l'intervention et de 86,2 [81,8­89,3] dB(A) après l'intervention (estimateur de Hodges-Lehmann, − 1,8 dB[A]; IC 95 %, − 3,3 à − 0,3; P = 0,02). La satisfaction des anesthésiologistes par rapport au bruit après l'intervention a été considérablement améliorée dans de nombreux domaines, y compris l'évaluation du bruit ayant distrait les anesthésiologistes. La satisfaction des patients était élevée avant l'intervention et ne s'est pas améliorée de manière significative. CONCLUSION: Dans ce projet d'amélioration de la qualité, les niveaux de bruit moyens lors de l'induction de l'anesthésie, la satisfaction des anesthésiologistes et la capacité perçue des anesthésiologistes à réaliser leurs tâches ont été améliorés à la suite d'un programme de formation multidisciplinaire sur la réduction du bruit en salle d'opération. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04204785); enregistrée le 19 décembre 2019.

The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. It comprises simple steatosis and non-alcoholic steatohepatitis (NASH), which can further progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD involves genetic, environmental, and endocrine factors, and several molecular mechanisms have been identified. In this review, we discuss the recent findings on the role of autophagy, in particular lipophagy and mitophagy, in hepatic lipid oxidation. We discuss the pre-clinical and clinical evidence suggesting that impairment of autophagy exacerbates NAFLD progression and restoration of autophagy exerts beneficial effects on NAFLD. We discuss how thyroid hormone (TH) simultaneously regulates lipophagy, mitophagy, and mitochondrial biogenesis to increase ß-oxidation of fatty acids and reduce steatosis in the liver. Lastly, we discuss the recent clinical progress in using TH or thyromimetics in treating NAFLD/NASH.

Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle.

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone α (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor α (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis, and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models were used in this study: TRα1PV/+ mice, which express the mutant Thra1PV gene ubiquitously, and SM-TRα1L400R/+ mice, which express TRα1L400R in a muscle-specific manner. Gastrocnemius muscle from TRα1PV/+, SM-TRα1L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (lysosomal-associated membrane protein [LAMP]-1 and LAMP-2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and estrogen-related receptor α (ERRα), key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins, were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired and was associated with decreased acylcarnitines and tricarboxylic acid cycle intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

Can Tissue Expansion Reconstruction in the Trunk of Children Increase the Risk of Scoliosis?

INTRODUCTION: We hypothesize that treatment of significant truncal lesions with truncal tissue expanders and subsequent flap surgery in pediatric patients may increase the risk of scoliosis. This study aims to investigate any relationship between tissue expansion (TE) and scoliosis and to compare the prevalence of scoliosis in our tissue expander population to the general population. METHODS: Health records of patients who underwent truncal TE at BC Children's Hospital between 1997 and 2017 were retrospectively reviewed and analyzed. The cross-sectional component of the study consisted of radiological imaging to establish the presence or absence of scoliosis. RESULTS: We identified 28 patients who underwent truncal TE over the study period. Ten had a scoliosis X-ray on their chart or as a part of the study. Three (10.7%) patients were identified as having developed scoliosis after TE. CONCLUSIONS: We recommend that pediatric TE patients be made aware of the potential complication of scoliosis and be followed closely in the years during and after their treatment, in order to allow for preventative measures, early diagnosis and early management (if required).

INTRODUCTION: Les chercheurs postulent que le traitement d'importantes lésions du tronc par des expandeurs tissulaires suivi d'une opération par lambeau chez les patients pédiatriques peut accroître le risque de scoliose. La présente étude vise à explorer la relation entre l'expansion tissulaire (ET) et la scoliose et à comparer la prévalence de scoliose entre la population ayant subi une expansion tissulaire et la population générale. MÉTHODOLOGIE: Les chercheurs ont procédé à l'analyse prospective du dossier de santé des patients qui ont subi une ET du tronc au BC Children's Hospital entre 1997 et 2017. L'élément transversal de l'étude était constitué d'une imagerie radiologique pour établir la présence ou l'absence de scoliose. RÉSULTATS: Les chercheurs ont recensé 28 patients qui ont subi une ET du tronc pendant la période de l'étude. Dix avaient une radiographie de scoliose au dossier ou en cours d'étude. Trois (10,7 %) avaient eu une scoliose après l'ET. CONCLUSIONS: Les chercheurs recommandent d'informer les patients pédiatriques qui subissent une ET du tronc qu'ils courent un risque de complication de scoliose et de les suivre de près dans les années où se déroulent le traitement et qui le suivent, afin de favoriser des mesures préventives, des diagnostics précoces et une prise en charge rapide, s'il y a lieu.

CD10 marks non-canonical PPARγ-independent adipocyte maturation and browning potential of adipose-derived stem cells.

BACKGROUND: Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. However, limitations in our understanding and the lack of reliable markers that can predict their maturation efficacies have hindered the development of stem cells as an effective therapeutic strategy. Our previous study identified CD10, a pro-adipogenic, depot-specific prospective cell surface marker of human adipose-derived stem cells (ASCs). Here, we aim to determine if CD10 can be used as a prospective marker to predict mature adipocyte quality and play a direct role in adipocyte maturation. METHODS: We first generated 14 primary human subject-derived ASCs and stable immortalized CD10 knockdown and overexpression lines for 4 subjects by the lentiviral transduction system. To evaluate the role of CD10 in adipogenesis, the adipogenic potential of the human subject samples were scored against their respective CD10 transcript levels. Assessment of UCP1 expression levels was performed to correlate CD10 levels to the browning potential of mature ASCs. Quantitative polymerase chain reaction (qPCR) and Western blot analysis were performed to determine CD10-dependent regulation of various targets. Seahorse analysis of oxidative metabolism and lipolysis assay were studied. Lastly, as a proof-of-concept study, we used CD10 as a prospective marker for screening nuclear receptor ligands library. RESULTS: We identified intrinsic CD10 levels as a positive determinant of adipocyte maturation as well as browning potential of ASCs. Interestingly, CD10 regulates ASC's adipogenic maturation non-canonically by modulating endogenous lipolysis without affecting the classical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent adipogenic pathways. Furthermore, our CD10-mediated screening analysis identified dexamethasone and retinoic acid as stimulator and inhibitor of adipogenesis, respectively, indicating CD10 as a useful biomarker for pro-adipogenic drug screening. CONCLUSION: Overall, we establish CD10 as a functionally relevant ASC biomarker, which may be a prerequisite to identify high-quality cell populations for improving metabolic diseases.

Hippo pathway effectors YAP and TAZ and their association with skeletal muscle ageing.

Skeletal muscle atrophy commonly occurs during ageing, thus pathways that regulate muscle mass may represent a potential therapeutic avenue for interventions. In this review, we explored the Hippo signalling pathway which plays an essential role in human oncogenesis and the pathway's influence on myogenesis and satellite cell functions, on supporting cells such as fibroblasts, and autophagy. YAP/TAZ was found to regulate both myoblast proliferation and differentiation, albeit with unique roles. Additionally, YAP/TAZ has different functions depending on the expressing cell type, making simple inference of their effects difficult. Studies in cancers have shown that the Hippo pathway influenced the autophagy pathway, although with mixed results. Most of the present researches on YAP/TAZ are focused on its oncogenicity and further studies are needed to translate these findings to physiological ageing. Taken together, the modulation of YAP/TAZ or the Hippo pathway in general may offer potential new strategies for the prevention or treatment of ageing.

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH.

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.

Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.

Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.

Previously developed senescent primary fibroblast models have limited relevance to study age-related changes in metabolically active tissues such as the liver. Here, we describe a protocol to generate senescent cells from the mouse hepatic cell line, AML12. These senescent cells exhibit molecular and metabolic signatures that are similar to those observed in livers from aged mice. These senescent AML12 cells should be a useful in vitro model to study the metabolic effects of aging in the liver. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).

Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.

The hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating kinase 1 (ULK1) in regulating the expression of the hepatic de novo cholesterol biosynthesis/MVA pathway genes. Genetic silencing of ULK1 in non-starved mouse (AML-12) and human (HepG2) hepatic cells as well as in mouse liver followed by transcriptome and pathway analysis revealed that the loss of ULK1 expression led to significant down-regulation of genes involved in the MVA/cholesterol biosynthesis pathway. At a mechanistic level, loss of ULK1 led to decreased expression of SREBF2/SREBP2 (sterol regulatory element binding factor 2) via its effects on AKT-FOXO3a signaling and repression of SREBF2 target genes in the MVA pathway. Our findings, therefore, discover ULK1 as a novel regulator of cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.

Autophagic protein ULK1 regulates FOXM1 signalling in human hepatoma cells.

Hepatocellular cancer (HCC) is one of the leading causes of mortality worldwide. Unfortunately, a limited choice of anti-cancer drugs is available for treatment, owing to their minimal efficacy and development of acquired resistance. Autophagy, a cellular survival pathway, often exhibits a pleiotropic role in HCC progression. Studies show increased autophagy in established HCC, promoting the survival of HCC cells in the tumour microenvironment. Therefore, novel anti-autophagy drugs hold promise for preventing HCC progression. Here, using a non-biased transcriptomics analysis in HepG2 cells we demonstrate the existence of an autophagy-FOXM1 nexus regulating growth in HepG2 cells. Additionally, we show that suppression of autophagy by an Unc-51 Like Autophagy Activating Kinase 1(ULK1) inhibitor not only attenuates the expression of FOXM1 and its transcriptional targets, but also has a synergistic effect on the inhibition of HepG2 growth when combined with FOXM1 inhibitors. Thus, the autophagic protein, ULK1, is a promising candidate for preventing HCC progression. Collectively, our results provide new insight into the role of autophagy in HCC growth and are a proof-of concept for combinatorial therapy using ULK1 and FOXM1 inhibitors.

Decreased autophagy and fuel switching occur in a senescent hepatic cell model system.

Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-ßGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from ß-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases.

The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.

Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase α catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, there is over-accumulation of hepatic glycogen and triglycerides that can lead to steatohepatitis and a risk for hepatocellular adenoma or carcinoma. Here, we examined the effects of the commonly used peroxisomal proliferated activated receptor α agonist, fenofibrate, on liver and kidney autophagy and lipid metabolism in 5-day-old G6pc -/- mice serving as a model of neonatal GSD Ia. Five-day administration of fenofibrate decreased the elevated hepatic and renal triglyceride and hepatic glycogen levels found in control G6pc -/- mice. Fenofibrate also induced autophagy and promoted ß-oxidation of fatty acids and stimulated gene expression of acyl-CoA dehydrogenases in the liver. These findings show that fenofibrate can rapidly decrease hepatic glycogen and triglyceride levels and renal triglyceride levels in neonatal G6pc -/- mice. Moreover, since fenofibrate is an FDA-approved drug that has an excellent safety profile, our findings suggest that fenofibrate could be a potential pharmacological therapy for GSD Ia in neonatal and pediatric patients as well as for adults. These findings may also apply to non-alcoholic fatty liver disease, which shares similar pathological and metabolic changes with GSD Ia.

Diagnosis and treatment of hypothyroidism in the elderly.

The global population is aging with millions of people today living into their 90 s. Thyroid disease, particularly hypothyroidism, is widespread among all age groups, and it is expected to steadily increase as the population gets older. Clinical diagnosis of hypothyroidism is challenging, as the TSH reference range needs to be evaluated according to age, while evaluation of TSH levels must also take into account body weight and other variants such as polypharmacy, comorbidities, and general health condition. Since thyroid hormone has a potent regulatory effect on cholesterol metabolism, the possibility of thyroid dysfunction should be considered in cases of unexplained dyslipidemia. Once hypothyroidism has been confirmed, treatment requires caution, frequent cardiovascular monitoring, and individualized (precision) medicine. Treatment of subclinical hypothyroidism (SCH) in the elderly should be undertaken with care, guided by age and the degree of SCH: a TSH higher than 10 mU/l seems a reasonable threshold, though it should be regularly re-evaluated, while the LT4 dose needs to be tailored, taking into account the patient's health condition and the potential presence of dyslipidemia as well as other metabolic derangements.

A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia.

Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor ß agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods:G6pc-/--deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers. Results: VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1α) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial ß-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and ß-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.

Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A1 (lysosomal v-type H+-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisomal lipid oxidation upon lysosomal inhibition. Mechanistically, pharmacological inhibition of lysosomes as well as genetic knockdown of Tfeb led to downregulation of the peroxisomal master regulator PPARA and its coactivator PPARGC1A/PGC1α. Consistently, ectopic induction of PPARA transcriptional activity rescues the effects of lysosomal inhibition on peroxisomal gene expression. Collectively, our results uncover a novel metabolic regulation of peroxisomes by lysosomes via PPARA-PPARGC1A transcriptional signalling. Abbreviations: Acox1: acyl-Coenzyme A oxidase 1, palmitoyl; Acot: acyl-CoA thioesterase; ACAA: acetyl-Coenzyme A acyltransferase; ABCD3/PMP70: ATP-binding cassette, sub-family D (ALD), member 3; BafA1: bafilomycin A1; Crot: carnitine O-octanoyltransferase; CTSB: cathepsin B; Decr2: 2-4-dienoyl-Coenzyme A reductase 2, peroxisomal; Ech1: enoyl coenzyme A hydratase 1, peroxisomal; Ehhadh: enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase; FDR: false discovery rate; Hsd17b4: hydroxysteroid (17-beta) dehydrogenase 4; NES: normalized enrichment score; NOM: nominal; Pex: peroxin; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; TFEB: transcription factor EB.