RESUMEN
Alteration in lipid metabolism plays a pivotal role in developing metabolic dysfunction-associated steatohepatitis (MASH). However, our understanding of alteration in lipid metabolism across liver zonation in MASH remains limited. Within this study, we investigated MASH-associated zone-specific lipid metabolism in a diet and chemical-induced MASH mouse model. Spatial lipidomics using mass spectrometry imaging in a MASH mouse model revealed 130 lipids from various classes altered across liver zonation and exhibited zone-specific lipid signatures in MASH. Triacylglycerols, diacylglycerols, sphingolipids and ceramides showed distinct zone-specific changes and re-distribution from pericentral to periportal localization in MASH. Saturated and monounsaturated fatty acids (FA) were the primary FA composition of increased lipids in MASH, while polyunsaturated FAs were the major FA composition of decreased lipids. We observed elevated fibrosis in the periportal region, which could be the result of observed metabolic alteration across zonation. Our study provides valuable insights into zone-specific hepatic lipid metabolism and demonstrates the significance of spatial lipidomics in understanding liver lipid metabolism. Identifying unique lipid distribution patterns may offer valuable insights into the pathophysiology of MASH and facilitate the discovery of diagnostic markers associated with liver zonation.
RESUMEN
Nonalcoholic fatty liver disease (NAFLD) has emerged as a public health concern. To date, the mechanism of NAFLD progression remains unclear, and pharmacological treatment options are scarce. Traditional animal NAFLD models are limited in helping address these problems due to interspecies differences. Liver chips are promising for modeling NAFLD. However, pre-existing liver chips cannot reproduce complex physicochemical microenvironments of the liver effectively; thus, NAFLD modeling based on these chips is incomplete. Herein, we develop a biomimetic liver lobule chip (LC) and then establish a more accurate on-chip NAFLD model. The self-developed LC achieves dual blood supply through the designed hepatic portal vein and hepatic artery and the microtissue cultured on the LC forms multiple structures similar to in vivo liver. Based on the LC, NAFLD is modeled. Steatosis is successfully induced and more importantly, changing lipid zonation in a liver lobule with the progression of NAFLD is demonstrated for the first time on a microfluidic chip. In addition, the application of the induced NAFLD model has been preliminarily demonstrated in the prevention and reversibility of promising drugs. This study provides a promising platform to understand NAFLD progression and identify drugs for treating NAFLD. STATEMENT OF SIGNIFICANCE: Liver chips are promising for modeling nonalcoholic fatty liver disease. However, on-chip replicating liver physicochemical microenvironments is still a challenge. Herein, we developed a liver lobule chip with dual blood supply, achieving self-organized liver microtissue that is similar to in vivo tissue. Based on the chip, we successfully modeled NAFLD under physiologically differentiated nutrient supplies. For the first time, the changing lipid zonation in a single liver lobule with the early-stage progression of NAFLD was demonstrated on a liver chip. This study provides a promising platform for modeling liver-related diseases.