MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice

• Published in: Scientific reports 2020-07, Vol.10 (1), p.12139-12139, Article 12139
• Main Authors: Leclère, Pierre S., Rousseau, Déborah, Patouraux, Stéphanie, Guérin, Sophie, Bonnafous, Stéphanie, Gréchez-Cassiau, Aline, Ruberto, Anthony A., Luci, Carmelo, Subramaniam, Malayannan, Tran, Albert, Delaunay, Franck, Gual, Philippe, Teboul, Michèle
• Format: Article
• Language: English
• Subjects: 631/443; 631/443/319; Animals; Apoptosis; Biomarkers - metabolism; Caspase 3 - metabolism; Caspase-3; Cells, Cultured; Choline; Choline - chemistry; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clock gene; Diet; Diet - veterinary; Disease Models, Animal; Diurnal; Early Growth Response Transcription Factors - deficiency; Early Growth Response Transcription Factors - genetics; Fatty liver; Fibrosis; Food and Nutrition; Gene expression; Hepatocytes; Hepatocytes - cytology; Hepatocytes - metabolism; Human health and pathology; Humanities and Social Sciences; Hépatology and Gastroenterology; Inflammation; Kruppel-Like Transcription Factors - deficiency; Kruppel-Like Transcription Factors - genetics; Life Sciences; Liver; Liver - injuries; Liver - metabolism; Liver - pathology; Male; Methionine; Methionine - chemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - pathology; Nutrient deficiency; Oscillations; Risk factors; Science; Science (multidisciplinary); Steatosis; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-69085-w

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.