Liver cell

About: Liver cell is a research topic. Over the lifetime, 10052 publications have been published within this topic receiving 293200 citations.

IKK-beta links inflammation to obesity-induced insulin resistance.

Abstract: Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.

Hepatitis B virus immunopathogenesis

Abstract: Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.

CORRELATED MORPHOMETRIC AND BIOCHEMICAL STUDIES ON THE LIVER CELL I. Morphometric Model, Stereologic Methods, and Normal Morphometric Data for Rat Liver

Abstract: The basic morphological properties of liver cells are defined in the form of a morphometric model to permit integrated quantitative characterization of functionally important parameters. Stereologic methods which allow efficient and reliable quantitative evaluation of sectioned liver tissue are presented. Material, obtained by a rigorous three-stage sampling procedure from five normal rat livers, is systematically subjected to this analysis at four levels of magnification. This yields quantitative data which are expressed as "densities," i.e. content per 1 ml of tissue, as "specific dimensions" related to 100 g body weight, and as absolute dimensions per average "mononuclear" hepatocyte. Base line data relating to the normal rat liver are presented for the entire spectrum of parameters. As examples, 1 ml of liver tissue contains 169 x 106 hepatocyte nuclei, some 90 x 106 nuclei of other cells, and 280 x 109 mitochondria. Hepatocyte cytoplasm accounts for 77% of liver volume, and the mitochondria for 18%. The surface area of endoplasmic reticulum membranes in 1 ml of liver tissue measures 11 m2 of which are ⅔ of the rough form carrying some 2 x 1013 ribosomes. The surface area of mitochondrial cristae in the unit volume is estimated at 6 m2. The validity and applicability of the method are discussed, and the data are compared with available information from other studies.

Somatic mutations of the beta -catenin gene are frequent in mouse and human hepatocellular carcinomas

Abstract: Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice.

Carbon tetrachloride hepatotoxicity

Abstract: During the past 20 years, study of the fatty liver induced by carbon tetrachloride has passed through 2 periods of revolutionary change, and at the present time a third revolutionary change is taking place. The dominant notion guiding most of the thinking before 1948 was that toxic and nutritional fatty liver disease could be understood in terms of failure in transport of fatty acids as phospholipids. As quantitative analyses of whole body phospholipid and neutral lipid metabolism became available through application of radioisotope technology, it became possible by 1953 to conclude that fatty acids were not transported in the plasma as phospholipids. For the next 6 years work in this field was dominated by the mitochondrial hypothesis. Carbon tetrachloride was thought to damage the liver cell mitochondria. It was suggested that lipid accumulation was due to a failure of normal pathways of lipid oxidation, and that death of the liver cells resulted from interruption in energy-transducing mechanisms. By 1959 this hypothesis also proved untenable since accumulation of triglycerides and degeneration of the hepatocellular endoplasmic reticulum preceeded mitochondrial degeneration by many hours. The major contribution of the work of this period was the introduction into the study of experimental hepatic toxicology of methods of biochemical cytology. A second revolutionary change took place in 1960. It became evident that carbon tetrachloride poisoning leads rapidly to cessation of movement of large quantities of triglycerides from the liver to the plasma. The blockade of hepatic triglyceride secretion by carbon tetrachloride accounts for the characteristic fatty liver. Earlier studies of rates of replacement of the different moieties of the plasma lipoproteins had demonstrated that low-density lipoprotein triglycerides were replaced much faster than the protein moiety. This work, as well as more recent studies combining use of the isolated, perfused liver with methods for separation of plasma protein and lipoprotein fractions, has made possible a most important new insight into the nature of hepatic triglyceride secretion. The latter can best be understood as a dual mechanism. One part of the mechanism involves hepatic biosynthesis of the various moieties of plasma low-density lipoproteins, coupling of these to form definitive lipoprotein molecules, and their extrusion to the plasma compartment. An auxiliary mechanism provides for re-entry into the system of triglyceride-free lipoprotein apoprotein. Movement of triglycerides from liver to plasma depends largely on the continuous functioning of the second, or auxiliary arm of the cycle. The knowledge that hepatic triglyceride secretion involves a dual mechanism has provided a powerful new guide for the analysis of mechanisms underlying fatty liver disease. In the case of carbon tetrachloride poisoning, the rapid onset of liver triglyceride accumulation most probably results mainly from cessation in function of the auxiliary coupling phase of hepatic triglyceride secretion, and less significantly from a breakdown in hepatic protein synthesis. During this period, ca . 1960 to 1965, highly provocative experimental findings led to an attempt to rationalize the hepatocellular necrosis and the triglyceride accumulation of carbon tetrachloride poisoning in terms of massive discharge of the sympathetic nervous system. The main evidence regarding the pathogenesis of hepatocellular necrosis was based on the observation that rats whose spinal cord had been divided were remarkably immune to the toxic agent. A review of the evidence does not support the contention that hepatocellular necrosis is a consequence of catecholamine discharge. The catecholamine hypothesis suggested that hepatic lipid accumulation is due to an oversupply of fatty acids mobilized from peripheral adipose tissue depots. Activation of the hypophyseal-adrenocortical axis has also been invoked in support of the peripheral oversupply hypothesis. A central requirement of this hypothesis must be that if oversupply of fatty acids is to be invoked as a significant factor in the pathogenesis of fatty liver, then the oversupply must be of sufficient magnitude and duration to account for the time course of the hepatic lipid accumulation. From this point of view the evidence offered in support of the peripheral oversupply hypothesis is not convincing. In particular, for carbon tetrachloride poisoning, at a time when liver triglycerides are increasing rapidly, there is no increase in flux of fatty acids through the plasma compartment. The most recent work in this field has inaugurated a third revolution in the study of carbon tetrachloride hepatotoxicity. Its essential feature is the recognition that carbon tetrachloride toxicity depends on cleavage of the carbon-tochlorine bond. At the same time, the long-held view that the toxic action of carbon tetrachloride resided in its effectiveness as a lipid solvent has finally been discarded. An important link has been established between the metabolism of carbon tetrachloride and the peroxidative decomposition of cytoplasmic membrane structural lipids. Sufficient data are not yet available to decide whether the latter effect is a major or minor consequence of the metabolism of carbon tetrachloride. The important point is that study of this problem has reached the organic chemical level of organization. This augurs well for the immediate future, which should witness further interesting new developments in the study of haloalkane toxicity.