Hepatic lipase: a pro- or anti-atherogenic protein?

Hepatic lipase (HL) plays a role in the metabolism of pro- and anti-atherogenic lipoproteins affecting their plasma level and composition. However, there is controversy regarding whether HL accelerates or retards atherosclerosis. Its effects on different lipoprotein classes show that, potentially, HL may promote as well as decrease atherogenesis. Studies in animals with genetically modulated HL expression show that it depends on the model used whether HL acts pro- or anti-atherogenic. In humans, HL activity seems to correlate inversely with atherosclerosis in (familial) hypercholesterolemia, and positively in hypertriglyceridemia. In normolipidemia, HL activity is weakly associated with coronary artery disease (CAD). Genetically low or absent HL activity is usually associated with increased CAD risk, especially if plasma lipid transport is impaired due to other factors. Since HL promotes the uptake of lipoproteins and lipoprotein-associated lipids, HL may affect intracellular lipid content. We hypothesize that the prime role of HL is to maintain, in concert with other factors (e.g., lipoprotein receptors), intracellular lipid homeostasis. This, and the uncertainties about its impact on human atherosclerosis, makes it difficult to predict whether HL is a suitable target for intervention to lower CAD risk. First, the physiological meaning of changes in HL activity under different conditions should be clarified.     

Role of Direct Repeat and Stem-Loop Motifs in mtDNA Deletions: Cause or Coincidence?

Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in degenerative and aging related conditions, such as sarcopenia and neuro-degeneration. While the precise molecular mechanism of deletion formation in mtDNA is still not completely understood, genome motifs such as direct repeat (DR) and stem-loop (SL) have been observed in the neighborhood of deletion breakpoints and thus have been postulated to take part in mutagenesis. In this study, we have analyzed the mitochondrial genomes from four different mammals: human, rhesus monkey, mouse and rat, and compared them to randomly generated sequences to further elucidate the role of direct repeat and stem-loop motifs in aging associated mtDNA deletions. Our analysis revealed that in the four species, DR and SL structures are abundant and that their distributions in mtDNA are not statistically different from randomized sequences. However, the average distance between the reported age associated mtDNA breakpoints and their respective nearest DR motifs is significantly shorter than what is expected of random chance in human (p<10(-4)) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) and rat (p = 0.0437), indicating the existence of species specific difference in the relationship between DR motifs and deletion breakpoints. In addition, the frequencies of large DRs (>10 bp) tend to decrease with increasing lifespan among the four mammals studied here, further suggesting an evolutionary selection against stable mtDNA misalignments associated with long DRs in long-living animals. In contrast to the results on DR, the probability of finding SL motifs near a deletion breakpoint does not differ from random in any of the four mtDNA sequences considered. Taken together, the findings in this study give support for the importance of stable mtDNA misalignments, aided by long DRs, as a major mechanism of deletion formation in long-living, but not in short-living mammals.     

Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: Cause or consequence?

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and refers to a spectrum of disorders ranging from steatosis to steatohepatitis, a disease stage characterized by inflammation, fibrosis, cell death and insulin resistance (IR). Due to its association with obesity and IR the impact of NAFLD is growing worldwide. Consistent with the role of mitochondria in fatty acid (FA) metabolism, impaired mitochondrial function is thought to contribute to NAFLD and IR. Indeed, mitochondrial dysfunction and impaired mitochondrial respiratory chain have been described in patients with non-alcoholic steatohepatitis and skeletal muscle of obese patients. However, recent data have provided evidence that pharmacological and genetic models of mitochondrial impairment with reduced electron transport stimulate insulin sensitivity and protect against diet-induced obesity, hepatosteatosis and IR. These beneficial metabolic effects of impaired mitochondrial oxidative phosphorylation may be related not only to the reduction of reactive oxygen species production that regulate insulin signaling but also to decreased mitochondrial FA overload that generate specific metabolites derived from incomplete FA oxidation (FAO) in the TCA cycle. In line with the Randle cycle, reduced mitochondrial FAO rates may alleviate the repression on glucose metabolism in obesity. In addition, the redox paradox in insulin signaling and the delicate mitochondrial antioxidant balance in steatohepatitis add another level of complexity to the role of mitochondria in NAFLD and IR. Thus, better understanding the role of mitochondria in FA metabolism and glucose homeostasis may provide novel strategies for the treatment of NAFLD and IR.     

Hypothyroidism as A Cause of Hyponatremia: Fact or Fiction?

ObjectiveTo illustrate that severe primary hypothyroidism alone may not be enough to cause hyponatremia in the otherwise healthy ambulatory patient.Methods:A retrospective chart review was conducted using an academic health center enterprise-wide electronic health record to identify 10 patients with primary hypo thyroidism and same-day serum thyroid-stimulating hormone (TSH), sodium, creatinine, and calculated glomerular filtration rate (GFR). Same-day free triiodothyronine or free thyroxine was also recorded if tested. Patients were included in our case series if they met the following inclusion criteria: TSH level > 100 μU/mL and same-day sodium and creatinine levels. All laboratory tests were collected on an outpatient basis.ResultsThe 10 subjects (2 men and 8 women) were ages 19 to 97 years (median, 51.5 years). Median TSH was 193 μU/mL (range, 104.2 to 515.6 μU/mL; normal, 0.40 to 5.50 μU/mL) with median sodium of 138 mmol/L (range, 136 to 142 mmol/L; normal, 135 to 146 mmol/L). The lowest sodium was 136 mmol/L with concurrent TSH of 469.7 μU/mL, free triiodothyronine of 1.0 pg/mL (normal, 1.8 to 4.6 pg/mL), and free thyroxine of 0.2 ng/ dL (normal, 0.7 to 1.8 ng/dL). Median GFR was 67.5 mL/ min/1.73 m² (range, 44 to 114 mL/min/1.73 m²; normal, 90 to 120 mL/min/1.73 m²).ConclusionIn our small series of patients with extreme TSH elevations, none had a serum sodium level below normal (< 135 mmol/L), even in the presence of a reduced GFR. Hyponatremia can be a common occurrence in hospitalized and/or chronically ill patients; however, in an otherwise relatively healthy ambulatory patient, hypothyroidism, even when severely undertreated, may be a less clinically relevant cause of hyponatremia. (Endocr Pract. 2012;18:894-897)     

Mitochondrial dysfunction in autism spectrum disorders: Cause or effect?

Autism Spectrum Disorders encompass severe developmental disorders characterized by variable degrees of impairment in language, communication and social skills, as well as by repetitive and stereotypic patterns of behaviour. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as (a) elevated lactate, pyruvate, and alanine levels in blood, urine and/or cerebrospinal fluid, (b) serum carnitine deficiency, and/or (c) enhanced oxidative stress. These biochemical abnormalities are accompanied by highly heterogeneous clinical presentations, which generally (but by no means always) encompass neurological and systemic symptoms relatively unusual in idiopathic autistic disorder. In some patients, these abnormalities have been successfully explained by the presence of specific mutations or rearrangements in their mitochondrial or nuclear DNA. However, in the majority of cases, abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent evidence from post-mortem studies of autistic brains points toward abnormalities in mitochondrial function as possible downstream consequences of dysreactive immunity and altered calcium (Ca²⁺) signalling.     

Flight Initiation Distance and Starting Distance: Biological Effect or Mathematical Artefact?

In many studies, flight initiation distance (FID, the distance at which a prey starts to flee at the approach of a walker) is positively related to starting distance (SD, the distance at which the walker begins to approach) and alert distance (AD, the distance at which the focal individual becomes alert to the threat). In spite of the fundamental differences between SD, a covariate that may not have any biological effect, and AD, a measure related to the behaviour of the animal, it is common to use SD as a proxy for AD when AD is hard to measure (e.g. in species that do not exhibit distinguishable alert postures). However, the relationship between SD and AD or FID may not have any biological reasons, but may instead simply result from a mathematical artefact because of the constraints SD ≥ AD ≥ FID. Under such constrains, the homoscedasticity assumption is violated, and thus, the classical null hypothesis of linear regression (slope = 0) is invalid. In this study, we first show that using SD as a proxy for AD can strongly affect the results on FID. Using data from FID tests on alpine marmots (Marmota marmota), a linear mixed model with AD as a covariate, suggested that the interaction between previous activity and AD had an effect on FID, while this effect was not detected when SD replaced AD as the covariate in the analysis. We then propose that the actual statistical test of the relationship between SD, AD and FID should be based on a null hypothesis that incorporates the constraint SD ≥ AD ≥ FID ≥ 0 and generate 95% CI of simulated slopes obtained from random values under this constraint. This null hypothesis can be rejected if the observed slope of the relationship between two of these variables is outside the 95% CI. We demonstrated that, for alpine marmots, the observed slope of the relationship between AD and SD was within the 95% CI of the simulated slopes. The absence of a statistically significant biological effect in the relationship between SD and AD raises important questions on the outcome of relationship between SD and FID. In Alpine marmot flight, decision should be studied separating the effect of SD on AD and the effect of AD on FID.     

Delaying and Extending Sleep During Weekends: Sleep Recovery or Circadian Effect?

There is a well-known tendency to delay and prolong our sleep during weekends (Saturday and Sunday), with an advance and reduction of sleep during workdays (Monday to Friday). The objective of this work was to determine if the changes of sleep during weekends are produced by a partial sleep deprivation or a lack of entraining of circadian rhythms to an advanced phase, during workdays. The subjects were 52 undergraduate female students, mean age = 17.5 years, SD = 1.32. All students attended school following a regular schedule, from Monday to Friday. Two groups of students were studied: one attended school from 07:00 to 12:00 h (morning group, n = 30); the other attended school from 14:00 to 18:00 (afternoon group, n = 22). None of the students worked or was engaged in other activity with a fixed schedule. All kept a sleep-wake diary for 2 weeks, in which they recorded their bedtimes, wakeup times, and sleep-onset latencies. The morning group delayed 47.4 min [t(29) = 4.72, p < 0.0001] and prolonged their sleep 118.2 min [t(29) = 9.4, p < 0.0001] during weekends. Although the afternoon group had the opportunity to maintain a delayed phase and a long sleep time throughout the week, they delayed their bedtime by 24 min [t(21) = 2.99, p < 0.01] during weekends, without changing their sleep duration. The findings suggest that the prolonged sleep during weekends is due to reduction of sleep during workdays, whereas the delay of bedtime seems to be associated with a tendency of the human circadian system to maintain a delayed phase     

Folate Deficiency after Anticonvulsant Drugs: An Effect of Hepatic Enzyme Induction?

Serum and red cell folate levels were reduced in 59% and 58% respectively of 75 children with epilepsy attending a residential school. The degree of folate deficiency was significantly related to increased hepatic microsomal enzyme activity, assessed from increased urinary excretion of D-glucaric acid and also correlated with the daily dose of anticonvulsant taken. Anticonvulsant drugs are known to have inducing properties, and since folate is required as a cofactor in drug hydroxylations it is suggested that folate depletion results from increased demand for the cofactor after induction of drug-metabolizing enzymes. As folate deficiency may ultimately limit drug metabolism this hypothesis would explain why blood phenytoin levels decrease and fit control may worsen after correction of folate deficiency in epileptic patients.     

Cardiac parasympathetic abnormalities: Cause or consequence of chagas heart disease?

The mechanisms by which Trypanosoma cruzi causes cardiomyopathy are unknown but are the subject o f several hypotheses. In this paper, Diego Davila, Osman Rossell and Jose Donis discuss the aetiology of cardiac failure in Chagas disease and suggest that parasympathetic abnormalities are a consequence of, rather than the cause of, the progressive cardiac enlargement seen in these patients.     

Vitamins, phytoplankton and bacteria: symbiosis or scavenging?

The conclusion that over 25% of global primary production dependson direct algal/bacterial symbiosis involving vitamin B₁₂ [Croftet al., (2005) Algae acquire vitamin B₁₂ through a symbioticrelationship with bacteria. Nature, 438, 90–93] is patentlyfalse, for it is based on a misconception of the probable levelof the vitamin B₁₂ requirement in marine pelagic algae. A reviewof the various published attempts at measuring this requirementsuggests that it is likely to be so low that oceanic and coastalconcentrations of the vitamin would usually be sufficient tosustain the populations that occur without the assistance ofdirect algal/bacterial symbiosis. The levels measured are discussedin relation to method (batch or continuous culture) and protocolsused. Requirement values considered by the author to be acceptablerange from 0.1 to 0.3 pM for the vitamin growth saturation constant(K_S) and from 30 to 100 µL algal biomass pmol^–1vitamin for the yield.     

Conchodontus,Mitrellataxis and Fungulodus: Conodonts,fish or both?

Conchodontus, Mitrellataxis and Fungulodus are phosphatic microfossils from the Late Devonian of China and North America, alternatively interpreted as conodont elements or fish scales. The histology and microornament of these sclerites have been studied in an attempt to resolve their affinity, and to determine characters for distinguishing between conodont elements and the ichthyoliths of other lower vertebrates. The histology of all three genera is directly comparable to conodont elements, dispelling the notion that conodonts are histologically indistinguishable from the teeth and scales of other vertebrates. Microornament is found not to be useful in discriminating between high-level taxonomic groupings. White matter and thickness of prismless enamel are suggested as apomorphies of the Conodonta.     

Idebenone and neuroprotection: antioxidant,pro-oxidant,or electron carrier?

Journal of Bioenergetics and Biomembranes - Ubiquinone, commonly called coenzyme Q10 (CoQ), is a lipophilic electron carrier and endogenous antioxidant found in all cellular membranes. In the...