Cellbound Pathologies 

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Nonalcoholic fatty liver disease (NAFLD) frequently progresses to liver fibrosis, an important indicator of clinical outcomes. As hepatic stellate cell activation dictates fibrosis development during NAFLD, pathways that mediate hepatic stellate cell activation and inactivation ultimately determine course of disease in NAFLD.

Hepatic stellate cells (HSCs) comprise a minor cell population in the liver but serve numerous critical functions in the normal liver and in response to injury. HSCs are primarily known for their activation upon liver injury and for producing the collagen-rich extracellular matrix in liver fibrosis. In the absence of liver injury, HSCs reside in a quiescent state, in which their main function appears to be the storage of retinoids or vitamin A-containing metabolites. Less appreciated functions of HSCs include amplifying the hepatic inflammatory response and expressing growth factors that are critical for liver development and both the initiation and termination of liver regeneration. Recent single-cell RNA sequencing studies have corroborated earlier studies indictaing that HSC activation involves a diverse array of phenotypic alterations

Dr.Dakota R. Kamm and Prof.Dr.Kyle S. McCommis

Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USA

Nonalcoholic fatty liver disease (NAFLD), for example, has been described to have structural and molecular changes in hepatic mitochondria. Furthermore, declines in mitochondrial function may contribute to increased mitochondrial cholesterol accumulation, which has been associated with the progression of steatosis to steatohepatitis. Evidence also suggests that the activation of hepatic stellate cells during hepatic fibrosis is associated with mitochondrial dysfunction. 

 Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury 

KCs are located in the hepatic sinusoids and lie inbetween or on top of endothelial cells. However, they do have direct cell contact with parenchymatous hepatocytes (HCs) through their cytoplasmic extensions. Cellular communication between KCs and HCs isthought to occur mainly by production of cytokines and excretion of inflammatory mediators such as eicosanoids, nitric oxide (NO), and/or reactive oxygen species (ROS) (8). Proinflammatory cytokines, in particular tumor necrosis factor (TNF)-a, interleukin (IL)-1,and IL-6 have been shown to be early and importantmediators of the hepatic inflammatory response. Thesecytokines induce the synthesis of acute phase proteinsand are also involved in the downregulation of xeno-biotic metabolizing enzyme systems such as cyto-chrome P-450 (CYP) and UDP glucuronosyl trans-ferase (UDPGT).  [ In relation to these paracrine factors involved in circuits of intercellular communication, the existence of a hepatic oxygen sensor located in the Kupffer cell has been postulated. According to this postulate the oxygen metabolism of the liver parenchymal cells could be under the control of the Kupffer cells.

The interference with the mitochondrial electron flow by some biomolecules released from the activated Kupffer cell, such as tumour necrosis factor, interleukins, eicosanoids, etc., would increase the rate of generation of reactive oxygen species by the inhibited mitochondrial respiratory chain.

Contributions | References

Juan C. Cutriâ, Susana Llesuy, Alberto Boveris 

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