Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites

Intraoperative molecular imaging of colorectal lung metastases with SGM-101:a feasibility study

Purpose: Metastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101. Methods: This was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score. Results: Thirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00–1.53), 1.45 (IQR: 1.00–1.89), and 4.81 (IQR: 2.70–7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12. Conclusion: This study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection. Trial registration: The study was registered in ClinicalTrial.gov under identifier NCT04737213 at February 2021.</p

Plasma Levels of Retinol Binding Protein 4 Relate to Large VLDL and Small LDL Particles in Subjects with and without Type 2 Diabetes

BACKGROUND: Retinol binding protein 4 (RBP4) carries retinol in plasma, but is also considered an adipokine, as it is implicated in insulin resistance in mice. Plasma RBP4 correlates with total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and may confer increased cardiovascular risk. However, controversy exists about circulating RPB4 levels in type 2 diabetes mellitus (T2DM) and obesity. Here, we analyzed the relationships of RBP4 and retinol with lipoprotein subfractions in subjects with and without T2DM. METHODS: Fasting plasma RBP4 (enzyme-linked immunosorbent assay) and retinol (high performance liquid chromatography) were assayed in 41 T2DM subjects and 37 non-diabetic subjects. Lipoprotein subfractions (NMR spectroscopy) were measured in 36 T2DM subjects and 27 non-diabetic subjects. Physical interaction of RBP4 with lipoproteins was assessed by fast protein liquid chromatography (FPLC). RESULTS: Plasma RBP4 and retinol were strongly correlated (r = 0.881, p 0.12), and were unrelated to body mass index. Notably, RBP4 and retinol were elevated in subjects with metabolic syndrome (p < 0.05), which was attributable to an association with elevated triglycerides (p = 0.013). Large VLDL, total LDL and small LDL were increased in T2DM subjects (p = 0.035 to 0.003). Taking all subjects together, RBP4 correlated with total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in univariate analysis (p < 0.001 for each). Age-, sex- and diabetes status-adjusted multivariable linear regression analysis revealed that RBP4 was independently associated with large VLDL (β = 0.444, p = 0.005) and small LDL particles (β = 0.539, p < 0.001). Its relationship with large VLDL remained after further adjustment for retinol. RBP4 did not co-elute with VLDL nor LDL particles in FPLC analyses. CONCLUSIONS: Plasma RBP4 levels are related to but do not physically interact with large VLDL and small LDL particles. Elevated RBP4 may contribute to a proatherogenic plasma lipoprotein profile

A Keck/DEIMOS spectroscopic survey of the faint M31 satellites And IX, And XI, And XII, and And XIII

We present the first spectroscopic analysis of the faint M31 satellite galaxies, AndXI and AndXIII, and a reanalysis of existing spectroscopic data for two further faint companions, And IX and AndXII. By combining data obtained using the DEIMOS spectrograph mounted on the Keck II telescope with deep photometry from the Suprime-Cam instrument on Subaru, we have calculated global properties for the dwarfs, such as systemic velocities, metallicites and half-light radii.We find each dwarf to be very metal poor ([Fe/H] -2 both photometrically and spectroscopically, from their stacked spectrum), and as such, they continue to follow the luminosity-metallicity relationship established with brighter dwarfs. We are unable to resolve a dispersion for And XI due to small sample size and low S/N, but we set a one sigma upper limit of sigma-v <5 km/s. For And IX, And XII and And XIII we resolve velocity dispersions of v=4.5 (+3.4,-3.2), 2.6(+5.1,-2.6) and 9.7(+8.9,-4.5) km/s, and derive masses within the half light radii of 6.2(+5.3,-5.1)x10^6 Msun, 2.4 (+6.5,-2.4)x10^6 Msun and 1.1(+1.4,-0.7)x10^7 Msun respectively. We discuss each satellite in the context of the Mateo relations for dwarf spheroidal galaxies, and the Universal halo profiles established for Milky Way dwarfs (Walker et al. 2009). For both galaxies, this sees them fall below the Universal halo profiles of Walker et al. (2009). When combined with the findings of McConnachie & Irwin (2006a), which reveal that the M31 satellites are twice as extended (in terms of both half-light and tidal radii) as their Milky Way counterparts, these results suggest that the satellite population of the Andromeda system could inhabit halos that are significantly different from those of the Milky Way in terms of their central densities (abridged).Comment: 26 pages, 18 figures, MNRAS submitte

The Distribution Of Heavy Elements In Spiral And Elliptical Galaxies

This review recaps significant results as they apply to non-dwarf galaxies, including the Milky Way, spiral disks and bulges, and elliptical and lenticular galaxies. Conclusions that span the galaxy types treated here are as follows. All galaxies, on average, have heavy element abundances (metallicities) that systematically decrease outward from their galactic centers while their global metallicities increase with galaxy mass. Abundance gradients are steepest in normal spirals and are seen to be progressively flatter going in order from barred spirals, lenticulars, and ellipticals. For spiral galaxies, local metallicity appears to be correlated with total (disk plus bulge) surface density. Observed abundance patterns indicate that N production is dominated by primary processes at low metallicity and secondary processes at high metallicity; C production increases with increasing metallicity; and O, Ne, S, and Ar are produced in lockstep independent of metallicity. In elliptical galaxies, nuclear abundances are in the range [Z/H] = 0.0 to 0.4, but the element mixture is not scaled-solar. In large elliptical galaxies [Mg/Fe] is in the range 0.3 to 0.5, decreasing to ~0 in smaller elliptical galaxies. Other light elements track the Mg enhancement, but the heavier Ca tracks Fe. Velocity dispersion appears to be a key parameter in the modulation of [Mg/Fe], but the cause of the connection is unclear.Comment: 55-page manuscript plus 16 figures. Invited review to appear in the Publications Of The Astronomical Society Of The Pacifi

The Bimodal Galaxy Stellar Mass Function in the COSMOS Survey to z~1: A Steep Faint End and a New Galaxy Dichotomy

We present a new analysis of stellar mass functions (MF) in the COSMOS field to fainter limits than has been previously probed to z~1. Neither the total nor the passive or star-forming MF can be well fit with a single Schechter function once one probes below 3e9 Msun. We observe a dip or plateau at masses ~1e10 Msun, and an upturn towards a steep faint-end slope of -1.7 at lower mass at any z<1. This bimodal nature of the MF is not solely a result of the blue/red dichotomy. The blue MF is by itself bimodal at z~1. This suggests a new dichotomy in galaxy formation that predates the appearance of the red sequence. We propose two interpretations for this bimodality. If the gas fraction increases towards lower mass, galaxies with M_baryon~1e10 Msun would shift to lower stellar masses, creating the observed dip. This would indicate a change in star formation efficiency, perhaps linked to supernovae feedback becoming much more efficient. Therefore, we investigate whether the dip is present in the baryonic (stars+gas) MF. Alternatively, the dip could be created by an enhancement of the galaxy assembly rate at ~1e11 Msun, a phenomenon that naturally arises if the baryon fraction peaks at M_halo ~1e12 Msun. In this scenario, galaxies occupying the bump around M* would be identified with central galaxies and the second fainter component having a steep faint-end slope with satellites. While the dip is apparent in the total MF at any z, it appears to shift from the blue to red population, likely as a result of transforming high-mass blue galaxies into red ones. At the same time, we detect a drastic upturn in the number of low-mass red galaxies. Their increase with time reflects a decrease in the number of blue systems and so we tentatively associate them with satellite dwarf galaxies that have undergone quenching.Comment: 16 pages, 10 figures, accepted for publication in Ap

Inside the whale: the structure and dynamics of the isolated Cetus dwarf spheroidal

This paper presents a study of the Cetus dwarf, an isolated dwarf galaxy within the Local Group. A matched-filter analysis of the INT/WFC imaging of this system reveals no evidence for significant tidal debris that could have been torn from the galaxy, bolstering the hypothesis that Cetus has never significantly interacted with either the Milky Way or M31. Additionally, Keck/Deimos spectroscopic observations identify this galaxy as a distinct kinematic population possessing a systematic velocity of $-87\pm2{\rm km\ s^{-1}}$and with a velocity dispersion of$17\pm2{\rm km s^{-1}}$; while tentative, these data also suggest that Cetus possesses a moderate rotational velocity of$\sim8{\rm km s^{-1}}$. The population is confirmed to be relatively metal-poor, consistent with${\rm [Fe/H]\sim-1.9}$, and, assuming virial equilibrium, implies that the Cetus dwarf galaxy possesses a$M/L\sim70$. It appears, therefore, that Cetus may represent a primordial dwarf galaxy, retaining the kinematic and structural properties lost by other members of the dwarf population of the Local Group in their interactions with the large galaxies. An analysis of Cetus's orbit through the Local Group indicates that it is at apocentre; taken in conjunction with the general dwarf population, this shows the mass of the Local Group to be$\gta2\times10^{12}M_\odot$.Comment: Accepted for publication in MNRA