Summary
This study investigated whether oxidized fatty acids derived from dietary linoleic acid contribute to liver damage and metabolic dysfunction in obese adolescents. Researchers examined 80 obese teenagers, measuring liver fat by MRI, blood markers of liver injury (including CK-18), circulating oxidized linoleic acid metabolites (such as 9-HODE, 13-HODE, 9-oxo-ODE, and 13-oxo-ODE), and indicators of glucose metabolism.
The findings showed that higher levels of oxidized linoleic acid metabolites were associated with liver cell injury—but only in adolescents who already had fatty liver (hepatic steatosis). In this group, elevated oxidized lipids strongly correlated with increased CK-18 levels, indicating greater liver damage. These oxidized fatty acids were also linked to impaired insulin secretion, and adolescents with type 2 diabetes had higher levels than those with normal or mildly impaired glucose tolerance. Additionally, a common genetic variant in PNPLA3 appeared to modify the relationship between oxidized lipids and liver injury, suggesting a gene–diet interaction.
Overall, the study supports a “second-hit” model of disease progression: fat accumulation in the liver creates vulnerability, and oxidation of n-6 fatty acids like linoleic acid generates harmful metabolites that promote inflammation, liver injury, and metabolic dysfunction. The results suggest that oxidized linoleic acid products may represent a mechanistic link between modern diets, pediatric NAFLD, and early-onset type 2 diabetes, and could be potential targets for prevention or treatment.
PMID: 23815500
PMCID: PMC3887421
DOI: 10.1089/ars.2013.5466
Abstract
In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3±3.31 years; body mass index 33.0±6.79 kg/m2), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D. Antioxid. Redox Signal. 20, 383–389.