• Sara Guerra, Gabriele Mocciaro, and Amalia Gastaldelli.
• Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy.
• Eur. J. Clin. Invest. 2022 Mar 1; 52 (3): e13695.

BackgroundThe prevalence of non-alcoholic fatty liver disease (NAFLD) is now 25% in the general population but increases to more than 55% in subjects with obesity and/or type 2 diabetes. Simple steatosis (NAFL) can develop into more severe forms, that is non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma leading to death.MethodsIn this narrative review, we have discussed the current knowledge in the pathophysiology of fatty liver disease, including both metabolic and non-metabolic factors, insulin resistance, mitochondrial function, as well as the markers of liver damage, giving attention to the alterations in lipid metabolism and production of lipotoxic lipids.ResultsInsulin resistance, particularly in the adipose tissue, is the main driver of NAFLD due to the excess release of fatty acids. Lipidome analyses have shown that several lipids, including DAGs and ceramides, and especially if they contain saturated lipids, act as bioactive compounds, toxic to the cells. Lipids can also affect mitochondrial function. Not only lipids, but also amino acid metabolism is impaired in NAFL/NASH, and some amino acids, as branched-chain and aromatic amino acids, glutamate, serine and glycine, have been linked to impaired metabolism, insulin resistance and severity of NAFLD and serine is a precursor of ceramides.ConclusionsThe measurement of lipotoxic species and adipose tissue dysfunction can help to identify individuals at risk of progression to NASH.© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

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