Abstract
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.
Highlights
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
To evaluate whether steatohepatitis features, including hepatic steatosis, inflammation and liver injury, display a circadian rhythmicity, WT mice were fed with a control diet (CD) or a methionine and choline deficient diet (MCDD) for 4 weeks
In response to TNFα/actinomycin D (ActD), Klf10-silenced primary hepatocytes displayed reduced cell viability (Fig. 5B) associated with a higher percentage of dead cells and early apoptotic cells. (Fig. 5C). These cells exhibited higher levels of activated caspase 3 (p17) in response to TNFα/ActD compared to control primary hepatocytes (Fig. 5D). These results suggest that hepatocytes lacking Klf[10] are more prone to apoptosis mediated by TNFα, which could support the aggravated liver injury observed in Klf10-/- mice upon MCDD challenge
Summary
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. Silencing Klf[10] 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. The essential amino acid methionine is required for the synthesis of S-adenosylmethionine (SAM) and glutathione, which are both antioxidants This model was widely used and despite the increasing numbers of reports linking circadian disorders and NAFLD, no study investigated the influence of the MCDD challenge on the circadian rhythmicity. We examine the steatohepatitis features around the 24-h cycle and the role of the circadian transcription factor KLF10 in the progression of the disease, in mice fed a MCDD
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