Abstract
Background and AimsA histopathological hallmark of chronic hepatitis B virus (HBV) infection is the presence of ground glass hepatocytes (GGHs). GGHs are liver cells that exhibit eosinophilic, granular, glassy cytoplasm in light microscopy and are characterized by accumulation of HBV surface (HBs) proteins in the endoplasmic reticulum (ER). More important, GGHs have been accepted as a precursor of HCC and may represent preneoplastic lesions of the liver.MethodsHere we show that the reason for ground glass phenotype of hepatocytes in patients with chronic hepatitis B (CHB) and in HBs transgenic mice is a complex formation between HBs proteins and lipid droplets (LDs) within the ER.ResultsAs fat is a main component of LDs their presence reduces the protein density of HBs aggregates. Therefore, they adsorb less amount of eosin during hematoxylin-eosin staining and appear dull in light microscopy. However, after induction of interferon response in the liver LDs were not only co-localized with HBs but also distributed throughout the cytoplasm of hepatocytes. The uniform distribution of LDs weakens the contrast between HBs aggregates and the rest of the cytoplasm and complicates the identification of GGHs. Suppression of interferon response restored the ground glass phenotype of hepatocytes.ConclusionsComplex formation between HBs and LDs represents a very important feature of CHB that could affect LDs functions in hepatocytes. The strain specific activation of the interferon response in the liver of HBs/c mice prevented the development of GGHs. Thus, manipulation of LDs could provide a new treatment strategy in the prevention of liver cancer.
Highlights
AND AIMS: A histopathological hallmark of chronic hepatitis B virus (HBV) infection is the presence of ground glass hepatocytes (GGHs)
Here we show that the reason for ground glass phenotype of hepatocytes in patients with chronic hepatitis B (CHB) and in HBV surface (HBs) transgenic mice is a complex formation between HBs proteins and lipid droplets (LDs) within the endoplasmic reticulum (ER)
The strain specific activation of the interferon response in the liver of HBs transgenic mice on BALB/c genetic background (HBs/c) mice prevented the development of GGHs
Summary
We show that the reason for ground glass phenotype of hepatocytes in patients with chronic hepatitis B (CHB) and in HBs transgenic mice is a complex formation between HBs proteins and lipid droplets (LDs) within the ER. The human tissue specimens were collected in the Institute for Pathology, University Clinic of Cologne, Germany (Biomasota 13-091), and the use was approved by the Ethics Commission of the University of Cologne (Az. 18052). Transgenic mice were maintained at the Central Animal Laboratory of the Justus Liebig University Giessen, Germany, under specified pathogen-free conditions. All experiments were approved by the Committee on the ethics of Animal Experiments of the Regierungspräsidium Giessen, Giessen, Germany (permit number: V54-19c 20 15 h 01 GI20/10 No 128/2014). Generation and characteristics of transgenic lineages Tg(Alb-1HBV), internal designation HBs/6, on C57BL/6 genetic background has been described previously.[42] These mice were crossed back to BALB/c genetic background for at least 8 generations. The transgenic mouse strain obtained was internally designed HBs/c
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