Heterogeneous acinar localization of the asialoglycoprotein internalization system in rat hepatocytes

Sluijs, Peter van der; Braakman, Ineke; Meijer, Dirk K. F.; Groothuis, Geny M. M.

doi:10.1002/hep.1840080609

Cited by 23 publications

(1 citation statement)

References 43 publications

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“…Notably, zonal heterogeneity of the ASGP receptor has been reported previously even if the results are not fully consistent. Autoradiography analysis of rat livers perfused ex vivo with the ligand 125 I-asialo-orosomucoid (ASOR) showed a higher uptake by the ASGP receptor in zone 3 than in zone 1 hepatocytes 40 . In contrast, McFarlane et al 41 found that the binding of antibodies to the ASGP receptor was higher in periportal areas in the rat liver.…”

Section: Discussionmentioning

confidence: 98%

Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Cansby

Nuñez-Durán

Magnusson

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity.MethodsWe developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids.ResultsWe found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet–induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis.ConclusionsThis study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD.

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Section: Discussionmentioning

confidence: 98%

Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Cansby

Nuñez-Durán

Magnusson

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Targeted therapy for hepatic cancer: Good in theory, problematic in practice

Wright

1989

Hepatology

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We present evidence that normal hepatocytes can be specifically protected from galactosamine toxicity in vitro by targeting an antagonist to these cells via receptor‐mediated endocytosis. The strategy is based upon the following principles: 1) galactosamine is a highly selective hepatotoxin that causes a dose‐dependent depletion of uridine intermediates; 2) galactosamine toxicity can be antagonized by supplemental administration of uridine; 3) normal hepatocytes possess unique cell‐surface receptors that can internalize galactose terminal (asialo‐) glycoproteins with subsequent degradation of the glycoprotein ligand. Based on these facts, we hypothesized that chemical coupling of a galactosamine antagonist to an asialoglycoprotein could result in cell‐specific delivery and protection of normal hepatocytes by targeting the antagonist via asialoglycoprotein receptors. Using a model system consisting of freshly isolated rat hepatocytes (receptor(+)) and Morris 7777 rat hepatoma (receptor (−)) cells, sensitivity to galactosamine in vitro was determined and found to be similar for both types of cells. A targetable antagonist was synthesized by coupling uridine monophosphate to asialoorosomucoid in a molar ratio of 5 to 1. Exposure of Morris 7777 cells to the targetable antagonist in the presence of a toxic concentration of galactosamine did not protect these cells as evidenced by a steady decline in the number of viable cells in a fashion identical to cells treated with galactosamine alone. However, normal hepatocytes that received the conjugate in the presence of galactosamine were protected as their viable cell number remained the same as control (untreated) cells. Competition by an excess of asialoglycoprotein inhibited the protective effect of the conjugate, supporting the concept that the asialoglycoprotein component of the conjugate was responsible for the specific delivery of the antagonist to the target cells.

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Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

et al. 1990

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Autoantibodies reacting with the galactose-specific hepatic asialoglycoprotein receptor--a liver-specific component expressed on the surfaces of hepatocytes--are often found in patients with chronic active hepatitis of presumed autoimmune origin. As part of an investigation into whether these anti-asialoglycoprotein receptor antibodies might be involved in the development of periportal liver damage in chronic active hepatitis, livers of ether-anesthetized rats were perfused in situ with polyclonal guinea pig anti-rabbit asialoglycoprotein receptor or murine monoclonal anti-human galactose-specific hepatic asialoglycoprotein receptor antibodies in excess at less than 8 degrees C or, as a control, with guinea pig anti-human plasma protein antibodies or normal guinea pig serum. Rapid (1 min) antegrade (by way of portal vein) or retrograde (through hepatic veins by way of vena cava) perfusions were performed in a nonrecirculating (once-through) mode in Ca+(+)-free medium. Blocks of liver tissue were immediately snap-frozen and the distribution of the antibody examined in cryostat sections by using an avidin-biotin immunohistochemical technique. In all of the perfusions with anti-asialoglycoprotein receptor (six antegrade, seven retrograde), the antibodies were found to be prominently and almost exclusively deposited on liver cells in the periportal areas. No deposition of immunoglobulins was detected in livers perfused with the control guinea pig sera. The findings suggest that the asialoglycoprotein receptor is expressed at high density mainly on cells in zone 1 of the hepatic lobule, and this may have implications for the development of periportal liver damage in chronic active hepatitis.

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Heterogeneous acinar localization of the asialoglycoprotein internalization system in rat hepatocytes

Cited by 23 publications

References 43 publications

Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease

Targeted therapy for hepatic cancer: Good in theory, problematic in practice

Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

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