Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

Abstract

We focus on hepatic inclusions, which are defined as intracellular aggregates of stainable substances. They represent established hallmarks of their respective human disorders, but unlike aggregates found in neurodegenerative disorders are often not well studied. Hepatic inclusions can be subdivided into primary liver aggregates and aggregates found in multiple tissues. The former ones consist of inclusions found in endoplasmic reticulum storage diseases such as α 1-antitrypsin aggregates or ground-glass hepatocytes, p62-containing (Mallory-Denk bodies and intracellular hyaline bodies) and porphyrin-containing inclusions. p62-containing aggregates are not restricted to the liver but are found in multiple other disorders such as Parkinson or Alzheimer disease. Inclusions such as pale bodies or intracellular hyaline bodies are typical for malignant disorders while others (ground-glass hepatocytes and α1-antitrypsin aggregates) are predominantly seen in non-neoplastic tissues. The inclusions, which are not restricted to the liver, are often due to a systemic viral infection, but also due to disruption of glycogen metabolism or systemic inclusion-forming diseases such as polyglutamine disorders or sarcoidosis. Despite their heterogeneity, inclusions share several pathogenic principles such as an imbalance between protein damage/misfolding on one side and repair/degradation on the other side. This is why hepatic aggregates represent a valuable tool to study the aggregation process in general and to improve our understanding of inclusions found in multiple human disorders.

Antimalarial Potential of Carica papaya and Vernonia amygdalina in Mice Infected with Plasmodium berghei

“…Histological examination of the liver cells in the treated groups showed the inability of the extract to clear the entire parasite inclusion from circulation and repair the hepatocyte, which agrees with the work of Stenad et al [26], who stated that hepatic inclusions are defined as intracellular aggregates of stainable substances which represent established hallmarks of their respective human disorder. Signs of regeneration/repairs of tissues using medicinal plants have been reported in other works [27, 28], which are consistent with the present study.…”

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

“…The cellular retention of mutated AAT (such as the Pi*Z variant) leads to a gain-of-function toxicity that appears to be proportional to the amount of retained protein 10. Notably, AAT constitutes an established acute phase protein that is induced in patients suffering from liver injury 41.…”

Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1–mediated p62/sequestosome 1 phosphorylation

“…Saturated fatty acids (SFAs) are major perpetrators of lipotoxic injuries to cells, whereas unsaturated fatty acids (UFAs) often confer protection against SFA‐induced lipotoxicity. NASH is characterized by various consequences of lipotoxic injury to liver cells, such as hepatocyte ballooning, protein inclusion formation, ectopic cell death, inflammation, and fibrosis . Obesity and NASH are also established risk factors for hepatocellular carcinoma (HCC) …”