👤 Antoni Gual

Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression. Show less

The need for a non-invasive diagnosis of the effects of ethanol in utero on the development of the intestine in humans led us to look for a serum marker of the structural integrity of the intestine. We propose apolipoprotein A-IV (apoA-IV) as a possible candidate. In humans this protein is synthesized only by intestinal mucosa, it is expressed in the enterocyte of the foetus from 20 weeks of gestation, and it is released to the blood stream after synthesis. We measured the levels of apoA-IV in the umbilical cord serum of neonates whose mothers had consumed alcohol during pregnancy and neonates born to women who had not (controls). The gestational age at delivery of the cases studied ranged from 36 to 42 weeks. ELISA and Western blot analysis were used. There was no difference in the mean body weight of neonates from either group. Nevertheless, exposure to ethanol in utero significantly reduced (by about 30%) the apoA-IV levels in serum at birth, regardless of body weight. Our findings suggest that circulating apoA-IV levels could be used as a clinical marker of the prenatal effects of ethanol on the structural integrity of the intestine. Neonatal diagnosis of these intestinal effects could improve post-natal outcome. Show less