The liver, conductor of cancer cachexia

Cachexia is a complex, multifactorial, frequent syndrome in cancer patients. Moreover, It affects between 50 %. Consequently, 80 % of patients according to the type of cancer, manifesting itself by involuntary and significant weight loss, linked to systemic metabolic disturbances. Furthermore, Beyond the significant alteration of quality of life, cachexy increases intolerance to treatments and mortality. For example, Cachexia would be responsible for around 20 % of cancer deaths. For example, No curative treatment has so far been available.

Tumor factors. Additionally, For example, derivatives of the host, such as certain cytokines (IL-6, GDF15, leukemia inhibitor factor), are recognized for their role in the stimulation of muscle and adipose catabolism. In addition, The precise role of the liver in cancer cachexia was however largely unknown. Nevertheless, despite its role in the systemic inflammatory response, the metabolism of amino acids and cellular energy regulation. Similarly, Recent liver, conductor cancer cachexia studies have linked cancer cachexia to alterations in liver function. inflammation, but molecular changes specific to hepatocytes have not been clearly identified, nor their contribution to the secretion of factors accelerating the melting of peripheral tissues.

The protective role of a factor of circadian rhythm

A recent study sheds new light on these points. The authors carried out a transcriptomic. epigenomic profiling of hepatocytes in several murin models of cancer with or without cachexia. The authors highlighted specific gene expression profiles in the liver. These distinct molecular signatures reveal significant activation of the metabolic pathways linked to acute inflammation. the treatment of amino acids. Even more. analyzes reveal a major involvement of the factors of the circadian rhythm, in particular Rev-Erbα, in the regulation of these signatures. Finally. it appears that the specific restoration of Rev-Erbα in the liver in mice carrying tumors reduces weight loss, muscle and greasy melting, without liver, conductor cancer cachexia modifying systemic inflammation.

Messengers of tissue destruction

The study reveals that the liver secretes several particularly harmful proteins in the context of cachexia: LBP (lipopolysaccharide binding protein). l’ITIH3 (inter-alpha-trypsin inhibitor heavy-chain H3), IGFBP1 (insulin-like growth factor binding protein 1) and the CXCL14. These hepatokines. the expression of which is normally hampered by Rev-Erbα, trigger in vitro Catabolism processes: muscle atrophy and adipocyte lipolysis. They actively participate in the observed tissue degradation in vainwhile their targeted inhibition in the liver reduces muscle. adipose melting in chatteries.

The authors validate these results by demonstrating plasma concentrations of LBP. ITIH3 and IGFBP1 systematically higher in patients with cancer of different types with cachexia, in negative correlation with weight loss.

They conclude that the identification of this “Rev-Erbα-Hépatokines” path as a lever of catabolism opens up unprecedented therapeutic perspectives to. fight cancer cachexia. Two complementary approaches then seem possible: the modulation of the liver circadian rhythm to restore liver, conductor cancer cachexia the activity of Rev-Erbα. the targeted inhibition of identified hepatokines.

This study modifies the understanding of the role of the liver in cachexia. by attributing it a central role of coordination of peripheral tissue degradation.