A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis (NASH) in mice via binding and relocating acetyl-coA carboxylase
Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drug targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, has been approved by FDA. Whether cytosolic ACC1 can be regulated spatially is unknown. Herein, we found that streptavidin, which is a bacterium derived tetrameric protein, forms cytosolic condensates and efficiently induce a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensates formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase (FASN). Notably, AAV mediated delivery of SA partially blocks mice liver DNL and ameliorate NASH without eliciting hypertriglyceridemia. In summary, our study demonstrates that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment. Overall design: To establish a fatty liver model, mice were fed a HFD diet (protein, 20%; fat, 60%; carbohydrates, 20%; #D12492, SYSE Bio-tech Co., LTD, Changzhou, China) for 24 weeks. To induce NASH, mice were fed a HFHC diet (protein, 14%; fat, 42%; carbohydrates, 44%; cholesterol, 0.2%; #TP26304, TROPHIC Animal Feed High-Tech Co. Ltd, Nantong, China) with free access to a mixture of 23.1% fructose and 18.9% sucrose in water solution for 16 weeks. Mice in the control group were fed a normal chow (NC) diet (protein, 20.6%; fat, 12.0%; carbohydrates,67.4 %; XIETONG BIO-ENGINEERING CO., LTD. Nanjing, China). AAV2/9-SA or AAV2/9-Ctrl (4.8X10^10vg per mouse, via tail vein) were administered to mice after 7 weeks of feeding.