Research On The Function And Mechanism Of Lipid Metabolism Regulating Liver Regeneration

It has been long observed that earlier phase of lipid accumulation is essential for later liver regeneration.However,it remains unclear whether this transient lipid accumulation can serve as signal molecules to enhance the regenerative capacity of hepatocytes except for simply providing building blocks to sustain cell proliferation.Using a high-throughput in vivo CRISPR screening,we identify MIER1 as a key epigenetic brake that senses the metabolism changes and remodels chromatin status to govern hepatocyte proliferation.We show that lipid accumulation causes alternation of the acute ER stress-PERK-EIF2 S axis,and consequently attenuated Mier1 translation.MIER1 downregulation in turn promotes cell cycle gene expression and regeneration through affecting chromatin remodeling.Importantly,animals with chronic liver steatosis become insensitive to hepatectomy induced lipid accumulation and have impaired coupling effect of MIER1 during regeneration;whereas MIER1 depletion greatly improves regeneration in these animals.Taken together,our studies reveal how the energy and the biomaterials— e.g.,supplied by lipids,and the epigenetic events are intimately intertwined to impact liver regeneration.