The mechanisms of steatosis pathogenesis during NASH development

Introduction In non-alcoholic fatty liver disease (NAFLD), imbalance between fatty acid uptake, synthesis and their combustion or secretion can lead to steatosis. In some patients, non-alcoholic fatty liver (NAFL) evolves in a more aggressive disease form called non-alcoholic steatohepatitis (NASH) which promotes the development of fibrosis. An unanswered question is whether mechanisms for steatosis are stable over time or whether a specific steatotic process occurs during NASH development and promotes disease progression. Aim Here, we wanted to define the mechanisms of liver fat accumulation at various stages of NAFLD progression in a well-established NASH mouse model. Methods Wildtype (WT) and FOZ -/- mice received either a normal diet or a high fat diet (HFD) for 0, 4, 12 or 32 weeks (n=4-8/group). Liver paraffin-embedded sections were used for NAFLD severity assessment, based on the NAFLD activity score (NAS) and the Sirius red staining (fibrosis). Total RNA was extracted from the liver and the visceral adipose tissue of WT and FOZ -/- mice for gene expression analysis of key pathways potentially involved in steatosis pathogenesis. Results FOZ -/- mice fed a HFD developed steatosis after 4 weeks, NASH after 12 weeks (NAS=8) and fibrotic NASH after 32 weeks (NAS=7 + presence of fibrosis). In contrast, only mild steatosis occurred in WT mice fed the HFD. In comparison with baseline situation (FOZ -/- 0 week), the transporter for extracellular fatty acid uptake (liver fatty acid transporter cluster of differentiation 36) significantly increased over time (p<0.01). Acetyl CoA oxidase, an enzyme of the peroxysomal β-oxidation was induced at early time point (4 weeks, p<0.01) and decreased thereafter (p<0,05). However, expression of carnitine palmitoyltransferase 1-α, a gene signing activation of mitochondrial β-oxidation was upregulated from week 4 and up to 32 weeks (p<0.05). De novo lipogenesis (DNL) assessed by stearoyl CoA desaturase 1 expression was stable over time. Apolipoprotein B expression, key for fatty acid export was initially upregulated during steatosis and NASH stages (p<0.01 at 4 and 12 weeks) but not at the fibrotic stage of the disease. Lipolytic enzymes adipose triglycerides lipase and hormone sensitive lipase in the epididymal white adipose tissue were upregulated in FOZ -/- HFD fed mice (p<0.01 and p<0.001, respectively) consistent with adipose tissue lipolysis at the NAFL and NASH stages. In contrast, in WT mice fed a HFD and developing only discrete steatosis over time, liver DNL was downregulated and no adipose tissue lipolysis was observed. Conclusion FOZ -/- develop fibrosing NASH over time due to an increased fatty acid transport to the liver, enhanced adipose tissue lipolysis, preserved de novo lipogenesis and at later timepoints downregulation of fatty acid export and defect in fatty acid oxidation. Those results open the possibility to evaluate targeted steatosis therapies according to NAFLD stage. Those pathways are currently investigated in HFD FOZ-/- mice supplemented in high fructose corn syrup as well as in human NAFLD with various disease severity.

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Lamotte, A., Leclercq, I., & Lanthier, N. (2020). The mechanisms of steatosis pathogenesis during NASH development. Acta Gastro-Enterologica Belgica, 83(1). https://hdl.handle.net/2078.5/169804 (Original work published 2020)