Elucidating the Metabolic Regulation of Liver Regeneration

The regenerative capability of liver is well known, and the mechanisms that regulate liver regeneration are extensively studied. Such analyses have defined general principles that govern the hepatic regenerative response and implicated specific extracellular and intracellular signals as regulated during and essential for normal liver regeneration. Nevertheless, the most proximal events that stimulate liver regeneration and the distal signals that terminate this process remain incompletely understood. Recent data suggest that the metabolic response to hepatic insufficiency might be the proximal signal that initiates regenerative hepatocellular proliferation. This review provides an overview of the data in support of a metabolic model of liver regeneration and reflects on the clinical implications and areas for further study suggested by these findings

Functional Relationships between Lipid Metabolism and Liver Regeneration

The regenerative capacity of the liver is well known, and the mechanisms that regulate this process have been extensively studied using experimental model systems including surgical resection and hepatotoxin exposure. The response to primary mitogens has also been used to investigate the regulation of hepatocellular proliferation. Such analyses have identified many specific cytokines and growth factors, intracellular signaling events, and transcription factors that are regulated during and necessary for normal liver regeneration. Nevertheless, the nature and identities of the most proximal events that initiate hepatic regeneration as well as those distal signals that terminate this process remain unknown. Here, we review the data implicating acute alterations in lipid metabolism as important determinants of experimental liver regeneration and propose a novel metabolic model of regeneration based on these data. We also discuss the association between chronic hepatic steatosis and impaired regeneration in animal models and humans and consider important areas for future research

Seasonal lags between organic carbon deposition and mineralization in marine sediments

The fate of phytoplankton detritus in the muddy sediments of shallow marine ecosystems was studied by labelling the water column of a 13 m3 microcosm with radiocarbon bicarbonate from January to July. By the end of the study, more than 9% of the original inorganic label was found as organic carbon in the top 10 cm of sediment. The accumulation of labelled organic carbon in the sediment totalled 14.5 gC/m2. We estimate that this amount represented 15% of daytime net primary production and roughly half of the labelled organic carbon that was deposited on the sediment. The finding of sedimentary carbon accumulation directly demonstrated that time lags on the order of months can exist between the deposition and mineralization of phytoplankton detritus in nature. Observed time lags may have occurred because heterotrophic activity was minimize by low winter and spring temperatures, pelagic and benthic grazing was minimal, and bioturbation rates were high. Mineralization of organic carbon may have been retarded by conditions in subsurface sediments. Detritus buried in the sediment during the winter and spring would have been available to the subsurface feeding benthos during the summer, when maximum metabolic demand occurs

Light Attenuation in Estuarine Mangrove Lakes

Submerged aquatic vegetation (SAV) cover has declined in brackish lakes in the southern Everglades characterized by low water transparencies, emphasizing the need to evaluate the suitability of the aquatic medium for SAV growth and to identify the light attenuating components that contribute most to light attenuation. Underwater attenuation of downwards irradiance of photosynthetically active radiation (PAR) was determined over a three year period at 42 sites in shallow (\u3c2 m depth) mangrove-surrounded lakes in two sub-estuaries in the coastal Everglades, Florida USA. Turbidity, chromophoric dissolved organic matter (CDOM), and phytoplankton chlorophyll a (chl a) were measured concurrently and their respective contributions to the light attenuation rate were estimated. Light transmission to the benthos relative to literature estimates of minimum requirements for SAV growth indicated that the underwater light environment was often unsuitable for SAV. Light attenuation rates (n = 417) corrected for solar elevation angles ranged from 0.16 m-1 to 9.83 m-1 with a mean of 1.73 m-1. High concentrations of CDOM with high specific light absorption contributed the most to light attenuation followed by turbidity and chl a. CDOM alone sufficiently reduces light transmission beyond the estimated limits for SAV growth, making it difficult for ecosystem managers to increase SAV abundance by management activities. Light limitation of SAV in these areas may be a persistent feature because of their proximity to CDOM source materials from the surrounding mangrove swamp. Increasing freshwater flow into these areas may dilute CDOM concentrations and improve the salinity and light climate for SAV communities

The effective potential, critical point scaling and the renormalization group

The desirability of evaluating the effective potential in field theories near a phase transition has been recognized in a number of different areas. We show that recent Monte Carlo simulations for the probability distribution for the order parameter in an equilibrium Ising system, when combined with low-order renormalization group results for an ordinary $\phi^4$ system, can be used to extract the effective potential. All scaling features are included in the process.Comment: REVTEX file, 22 pages, three figures, submitted to Phys. Rev.

Diet modifies pioglitazone’s influence on hepatic PPARγ-regulated mitochondrial gene expression

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation

A comparison of system (O\u3csub\u3e2\u3c/sub\u3e and CO\u3csub\u3e2\u3c/sub\u3e) and C-14 measurements of metabolism in estuarine mesocosms

Metabolism in estuarine mesocosms was measured by total system oxygen and carbon dioxide and by C-14 bottle incubations to determine the effects of nutrient enrichment (6 levels) over a 9 mo period. These data provided an unprecedented opportunity for calculating metabolic ratios (photosynthetic quotient [P.Q.] and respiratory quotient [R.Q.]) based on the 3 measures of metabolism and determining the impact of other system processes. System metabolism ratios based on daily data varied from 0 to 5.0. System metabolism ratios of P.Q. and R Q. based on integrated data were highly correlated (r = 0.95 to 0.96) and similar to traditional ratios obtained in phytoplankton studies. A system photosynthetic quotient of 1.2 and a system respiratory quotient of 1.1 were calculated from the integrated data. These ratios were only slightly affected by carbon dioxide diffusion and 3 benthic processes: denitrification, sulfur metabolism and calcium carbonate dissolution. There was no trend for system metabolism ratios up the nutrient gradient. The C-14 estimations of productivity appeared nitrogen limited in the lower nutrient treatments and provided lower estimates than the 2 system measures of production

Statics and Dynamics of an Interface in a Temperature Gradient

The response and nonconserved dynamics of a two-phase interface in the presence of a temperature gradient oriented normally to the interface are considered. Two types of boundary conditions on the order parameter are considered, and the structure of the effective free energy and the Langevin equation for the collective coordinate specifying the interface position are analyzed.Comment: 15 pages, Revtex 3.0, 5 figures available upon reques

Measuring the Cluster Magnetic Field Power Spectra from Faraday Rotation Maps of Abell 400, Abell 2634 and Hydra A

We apply a novel technique of Faraday Rotation measure (RM) map analysis to three galaxy clusters, Abell 400, Abell 2634 and Hydra A, in order to estimate cluster magnetic field strengths, length scales and power spectra. This analysis is based on the assumption that the magnetic fields are statistically isotropically distributed across the Faraday screen. We investigate the difficulties involved in the application of the analysis to observational data. We derive magnetic power spectra for the three clusters and discuss influences on their shapes. We show that magnetic fluctuations are probed on length scales ranging over at least one order of magnitude. Using this range for the determination of central cluster magnetic field strength yields 3 muG in Abell 2634, 6 muG in Abell 400 and 12 muG in Hydra A. The magnetic field autocorrelation length was determined to be 4.9 kpc for Abell 2634, 3.6 kpc for Abell 400 and 0.9 kpc for Hydra A. We show that the RM autocorrelation length is larger than the magnetic field autocorrelation length. We investigate in a response analysis if it is possible to determine spectral slopes of the power spectra. We find that integrated numbers can be determined from this analysis but differential parameters such as spectral slopes have to be treated differently. Our response analysis results in spectral slopes of the power spectra of spectral indices alpha = 1.6 to 2.0 suggesting that Kolmogorov spectra are possible but flatter spectral slopes than alpha = 1.3 can be excluded.Comment: 14 pages, 9 figures, accepted by A&

GATA6 modulates the ductular reaction to bile duct ligation

Background GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion. Methods The murine Gata6 gene was conditionally deleted using Alb-cre, a transgene expressed in hepatoblasts (the precursors of hepatocytes and cholangiocytes) and mature hepatocytes. Bile duct ligation (BDL) was used to model biliary obstruction. Results Alb-Cre;Gata6(flox/flox) mice were viable and fertile. Cre-mediated recombination of Gata6 in hepatocytes had little impact on cellular structure or function. GATA6 immunoreactivity was retained in a majority of biliary epithelial cells in adult Alb-Cre;Gata6(flox/flox) mice, implying that surviving cholangiocytes were derived from hepatoblasts that had escaped biallelic Cre-mediated recombination. Although GATA6 immunoreactivity was preserved in cholangiocytes, Alb-cre;Gata6(flox/flox) mice had a demonstrable biliary phenotype. A neutrophil-rich infiltrate surrounded newly formed bile ducts in neonatal Alb-Cre;Gata6(flox/flox) mice. Foci of fibrosis/necrosis, presumed to reflect patchy defects in bile duct formation, were observed in the livers of 37% of adult Alb-cre;Gata6(flox/flox) mice and 0% of controls (p <0.05). Most notably, Alb-cre;Gata6(flox/flox) mice had an altered response to BDL manifest as reduced survival, impaired bile ductule proliferation, increased parenchymal necrosis, reduced fibrosis, and enhanced macrophage accumulation in the portal space. Conclusions GATA6 orchestrates intrahepatic biliary remodeling and mitigates liver injury following extrahepatic bile duct obstruction. Graphic abstractPeer reviewe