Summary Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver ...sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.
Although it is known that obesity increases the risk of endometrial cancer and is linked to higher mortality rates in the general population, the association between obesity and mortality among ...endometrial cancer survivors is unclear. We performed a medline search using exploded Mesh keywords 'endometrial neoplasms/' and ('body mass index/' or 'obesity/') and ('survival analysis/' or 'mortality/' or (survivor* or survival*).mp.). We also inspected bibliographies of relevant papers to identify related publications. Our search criteria yielded 74 studies, 12 of which met inclusion criteria. Four of the included studies reported a statistically or marginally significant association between obesity and higher all cause mortality among endometrial cancer survivors after multivariate adjustment. The suggestive association between body mass index and higher all cause mortality among women with endometrial cancer was comparable to the magnitude of association reported in prospective studies of healthy women. Of the five studies that examined progression-free survival and the two studies reporting on disease-specific mortality, none reported an association with obesity. Future studies are needed to understand disease-specific mortality, the importance of obesity-onset timing and whether mechanisms of obesity-related mortality in this population of women differ from those of the general population.
We announce the discovery of the Crater 2 dwarf galaxy, identified in imaging data of the VLT Survey Telescope ATLAS survey. Given its half-light radius of ∼1100 pc, Crater 2 is the fourth largest ...satellite of the Milky Way, surpassed only by the Large Magellanic Cloud, Small Magellanic Cloud and the Sgr dwarf. With a total luminosity of M
V
≈ −8, this galaxy is also one of the lowest surface brightness dwarfs. Falling under the nominal detection boundary of 30 mag arcsec−2, it compares in nebulosity to the recently discovered Tuc 2 and Tuc IV and UMa II. Crater 2 is located ∼120 kpc from the Sun and appears to be aligned in 3D with the enigmatic globular cluster Crater, the pair of ultrafaint dwarfs Leo IV and Leo V and the classical dwarf Leo II. We argue that such arrangement is probably not accidental and, in fact, can be viewed as the evidence for the accretion of the Crater-Leo group.
Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of ...unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
We announce the discovery of a new satellite of the Milky Way in the constellation of Bootes at a distance of 660 kpc. It was found in a systematic search for stellar overdensities in the north ...Galactic cap using Sloan Digital Sky Survey Data Release 5. The color-magnitude diagram shows a well-defined turnoff, red giant branch, and extended horizontal branch. Its absolute magnitude is M sub(v) 6 -5.8 mag, which makes it one of the faintest galaxies known. The half-light radius is 6220 pc. The isodensity contours are elongated and have an irregular shape, suggesting that Boo may be a disrupted dwarf spheroidal galaxy.
Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A ...key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.
Myocardial ischaemia reperfusion injury is the leading cause of death in patients with cardiovascular disease. Interventions such as ischaemic pre and postconditioning protect against myocardial ...ischaemia reperfusion injury. Certain anaesthesia drugs and opioids can produce the same effects, which led to an initial flurry of excitement given the extensive use of these drugs in surgery. The underlying mechanisms have since been extensively studied in experimental animal models but attempts to translate these findings to clinical settings have resulted in contradictory results. There are a number of reasons for this such as dose response, the intensity of the ischaemic stimulus applied, the duration of ischaemia and lost or diminished cardioprotection in common co-morbidities such as diabetes and senescence. This review focuses on current knowledge regarding myocardial ischaemia reperfusion injury and cardioprotective interventions both in experimental animal studies and in clinical trials.
We announce the discovery of the Aquarius 2 dwarf galaxy, a new distant satellite of the Milky Way, detected on the fringes of the VLT Survey Telescope (VST) ATLAS and the Sloan Digital Sky Survey ...(SDSS) surveys. The object was originally identified as an overdensity of red giant branch stars, but chosen for subsequent follow-up based on the presence of a strong blue horizontal branch, which was also used to measure its distance of ∼110 kpc. Using deeper imaging from the Inamori-Magellan Areal Camera and Spectrograph camera on the 6.5m Baade and spectroscopy with DEep Imaging Multi-Object Spectrograph on Keck, we measured the satellite's half-light radius 5.1 ± 0.8 arcmin, or ∼160 pc at this distance, and its stellar velocity dispersion of
$5.4^{+3.4}_{-0.9}$
km s−1. With μ = 30.2 mag arcsec−2 and M
V = −4.36, the new satellite lies close to two important detection limits: one in surface brightness; and one in luminosity at a given distance, thereby making Aquarius 2 one of the hardest dwarfs to find.
In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We performed gel filtration of ...liver supernatants and identified two protein fractions, designated Y and Z, which bound organic anions including bilirubin, and thus we proposed that they were involved in hepatic uptake of organic anions from plasma. Subsequently, the Y and Z proteins responsible for this binding activity were purified, cloned, and sequenced. With Bill Jakoby, we identified Y protein as a member of the glutathione S-transferase (GST) protein family. In separate studies, Z was found to be a member of the fatty acid–binding protein (FABP) family. These proteins have since been shown to have additional surprising roles, but understanding of their full role in physiology and disease has not yet been achieved.
In the 1960s, bilirubin metabolism was a “hot” topic. Along with other groups, my lab was studying various forms of inheritable jaundice in an effort to dissect the mechanism of bilirubin's transfer from plasma into the hepatocyte and its role in intracellular metabolism and biliary secretion. These processes were eventually identified and found to be related to the basic mechanisms whereby the liver handles many anionic drugs, metabolites, and hormones. Because the mechanism of hepatic uptake of bilirubin was unknown, A.J. Levi, Z. Gatmaitan, and I took advantage of advances in gel permeation chromatography to study this process. In 1969, we described two hepatic cytoplasmic protein fractions, designated Y and Z, that bound bilirubin and various organic anionic dyes in vivo and in vitro and, based on tissue distribution, abundance, and effects of genetic and pharmacologic models, were proposed to participate in organic anion uptake (Levi et al., 1969) 1. In the decades since then, the Y and Z proteins have been identified as members of large protein families that were cloned and sequenced. Several surprising functions emerged, whereas others are proposed based on binding properties. Many challenges remain in understanding the full role of these proteins in physiology and disease.
We present the first results of our search for new, extended planetary nebulae (PNe) based on careful, systematic, visual scrutiny of the imaging data from the Isaac Newton Telescope Photometric H ...alpha Survey of the Northern Galactic plane (IPHAS). The newly uncovered PNe will help to improve the census of this important population of Galactic objects that serve as key windows into the late-stage evolution of low- to intermediate-mass stars. They will also facilitate study of the faint end of the ensemble Galactic PN luminosity function. The sensitivity and coverage of IPHAS allows PNe to be found in regions of greater extinction in the Galactic plane and/or those PNe in a more advanced evolutionary state and at larger distances compared to the general Galactic PN population. Using a set of newly revised optical diagnostic diagrams in combination with access to a powerful, new, multiwavelength imaging data base, we have identified 159 true, likely and possible PNe for this first catalogue release. The ability of IPHAS to unveil PNe at low Galactic latitudes and towards the Galactic Anticentre, compared to previous surveys, makes this survey an ideal tool to contribute to the improvement of our knowledge of the whole Galactic PN population.
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