The physiological response to
starvation involves increased muscle proteolysis and adipose tissue lipolysis that supply
amino acids and non-
esterified fatty acids ('
free fatty acids') for gluconeogenesis, oxidation and ketogenesis. In the present issue of Clinical Science, Moller and co-workers show that, in humans, IHL (intrahepatic
lipid) content, measured using (1)H-magnetic resonance spectroscopy, increases following 36 h of fasting, with a direct association with plasma levels of
3-hydroxybutyrate. The observation raises interesting questions as to how IHL levels increase in a situation of increased mitochondrial
fatty acid oxidation and ketogenesis. Possible mechanisms for increased IHLs include reduced
apoB-100 (apolipoprotein B-100) production and hepatic
lipid export, and/or impaired mitochondrial function resulting from increased oxidative stress, with diversion of
fatty acids for esterification. The accumulation of IHL during prolonged fasting may, therefore, reflect a maladaptive response to increased non-
esterified fatty acid delivery to the liver that unmasks a subtle defect in mitochondrial function. This could have implications for the pathogenesis of the common human disorder of
non-alcoholic fatty liver disease. The accumulation of IHLs observed with prolonged fasting may also explain exacerbations of
steatohepatitis seen sometimes with rapid
weight loss,
anorexia nervosa and
parenteral nutrition. The findings also suggest caution against promoting excessive ketogenesis with
weight-loss regimens.