Comprehensive lipidomics reveals reduced hepatic lipid turnover in NAFLD during alcohol intoxication

Background & Aims In experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication. Methods We studied 39 participants with three distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 minutes. Hepatic and systemic venous blood were sampled simultaneously at three time points: baseline, 60 and 180 min after alcohol intervention. Liver biopsies were sampled 240 minutes after alcohol intervention. We used ultra-high-performance liquid chromatograph mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples. Results After alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, while LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared to systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD. Conclusions Alcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD.