Lipidomic signatures discriminate subtle hepatic changes in the progression of porcine nonalcoholic steatohepatitis.

Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts (CS, MAT1A, and SPP1) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism.NEW & NOTEWORTHY A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.

Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model.

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH.