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Rôle du facteur de transcription circadien Krüppel-Like Factor 10 (KLF 10) dans le développement des complications hépatiques de l’obésité

Abstract : Non-alcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver diseases (NAFLDs), is a global public health problem without approved pharmacological therapy. NAFLD extend from non-pathogenic lipid accumulation, known as hepatic steatosis to hepatocellular carcinoma (HCC) through a wide spectrum of stages including NASH and fibrosis. NASH is featured by hepatic inflammation and hepatocyte cell death. Better understand NASH pathogenic cellular and molecular mechanisms is an important clinical requirement.Circadian timing system (CTS) is the main synchronizer of organismal physiology to environmental light/dark cycles. This CTS is comprised of a central pacemaker in the supra-chiasmatic nucleus of the hypothalamus and peripheral clocks localized in each single cell throughout the brain and body. Western society life style, including junk food consumption and erratic feeding, chronic jet lag, light exposure at night and shift-work, can disrupt the CTS. CTS disruption has been assessed as a risk factor for the development of chronic diseases including metabolic syndrome and cancer. The liver is the most rhythmic organ and evidence for an intricate link between CTS disruption and NAFLD development is most illustrated by (i) the genetic and environmental disruption of the CTS leads to dyslipidemia, hepatic steatosis as well as spontaneous NASH and HCC development (ii) the circadian hepatic transcriptome is rearranged in mice fed high fat diet and displaying hepatic steatosis, showing that metabolic disruption also impacts diurnal oscillation of transcripts. Krüppel-like factor 10 is a circadian transcription factor directly regulated by the circadian clock in the liver and help shaping the hepatic diurnal transcriptome and the control carbohydrate and lipid metabolism homeostasis. Beside from metabolism, this transcription factor has also been shown to regulate two NASH related processes, in very different contexts, namely inflammation and cell death. We thus aimed to evaluate the implication of circadian rhythms and the role of KLF10 during steatohepatitisHere, 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 oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. Klf10 deficient mice (Klf10-/-) display enhanced liver injury despite the same level of hepatic steatosis and inflammation that control mice upon MCDD challenge. Specific genetic ablation of Klf10 only in hepatocytes phenocopied the phenotype of Klf10-/- mice upon MCDD. Silencing Klf10 in isolated primary hepatocytes also sensitized these cells to apoptosis along with increased caspase 3 activation in response to TNFα. We also show that the hepatic KLF10 expression correlates with liver injury (ALT activity) and the circulating keratin 18 hepatocyte death marker in a cohort of obese patients. Collectively our findings suggest that specific NASH features including steatosis and inflammation display diurnal oscillations and the associated altered circadian expression of Klf10 may aggravate liver injury through hepatocyte sensitization to cell death.Collectively, our results gathered from cellular and animal experiments as well as correlative study in Human indicate that hepatic steatosis and inflammation could be rhythmic during NASH and that KLF10 could be a hepatoprotective factor that could limit NAFLD progression.
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Submitted on : Friday, December 3, 2021 - 1:01:23 AM
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  • HAL Id : tel-03464117, version 1

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Pierre Leclère. Rôle du facteur de transcription circadien Krüppel-Like Factor 10 (KLF 10) dans le développement des complications hépatiques de l’obésité. Biologie moléculaire. COMUE Université Côte d'Azur (2015 - 2019), 2019. Français. ⟨NNT : 2019AZUR6030⟩. ⟨tel-03464117⟩

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