Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet

PLoS One. 2023 Jun 2;18(6):e0286726. doi: 10.1371/journal.pone.0286726. eCollection 2023.


Increased uptake of fat, such as through the ingestion of high fat diet (HFD), can lead to fatty liver diseases and metabolic syndrome. It is not clear whether certain fatty acids may be more pathogenic than others to the liver. Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in the Western diet and its excessive consumption can lead to increased lipid peroxidation. We hypothesized that a high level of LA in HFD will contribute significantly to the hepatic steatosis and injury, whereas vitamin E (VIT-E) may reverse the effects from LA by inhibiting lipid peroxidation. To test this hypothesis, we fed mice with the following diets for 20 weeks: a standard low-fat diet (CHOW), HFD with a low level of LA (LOW-LA, 1% of energy from LA), HFD with a high level of LA (HI-LA, 8% of energy from LA), or HI-LA diet with VIT-E supplement (HI-LA + VIT-E). We found that the HI-LA diet resulted in more body weight gain, larger adipocyte area, and higher serum levels of triglycerides (TG) and free fatty acids (FFA) relative to the CHOW and LOW-LA diets. In mice fed with the HI-LA diet, severer hepatic steatosis was seen with higher levels of hepatic TG and FFA. Expression of genes related to lipid metabolism was altered in the liver by HI-LA diet, including fibroblast growth factor 21 (Fgf21), cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase 1 (Scd1), and acyl-CoA oxidase 1 (Acox1). Liver injury, inflammation and fibrotic response were all enhanced in mice fed with the HI-LA diet when compared with the LOW-LA diet. Notably, addition of VIT-E supplement, which restores the proper VIT-E/PUFA ratio, significantly reduced the detrimental effects of the high level of LA. Taken together, our results suggest that a high level of LA and a low ratio of VIT-E/PUFA in HFD can contribute significantly to metabolic abnormalities and hepatic injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diet, High-Fat* / adverse effects
  • Fatty Acids, Nonesterified / metabolism
  • Fatty Acids, Unsaturated / metabolism
  • Linoleic Acid / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Triglycerides
  • Vitamin E / metabolism


  • Linoleic Acid
  • Vitamin E
  • Triglycerides
  • Fatty Acids, Unsaturated
  • Fatty Acids, Nonesterified