Comment on "Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production, and editorial in the same journal by RM Krauss, Hold the antioxidants and improve plasma lipids?"
M. Pan et al., JCI 113: 1253-55 (Mai 2004)
The study by M Pan et al raises an interesting hypothesis that reducing oxidative stress in the liver by antioxidants may increase plasma lipids. The experiments in rodent liver cells suggest that the lipid-lowering effect of polyunsaturated fatty acids (PUFA) can be blunted by antioxidants like vitamin E.
Studies in human subjects, animals and in vitro however support an important role of vitamin E in reducing CVD risk, i.e. inhibition of LDL oxidation, anti-inflammatory effects (CRP-lowering), inhibiting platelet aggregation. This is corroborated by a plethora of observational trials that suggest benefits of high vitamin E intakes. Thus, the totality of evidence favors beneficial effects of vitamin E in the prevention of CVD.
Mechanistic studies in cells are suggestive but not conclusive and cannot readily translated into the human situation. The present study offers one explanation on how n-3-PUFA contribute to the lowering of plasma lipids. PUFA increase oxidative stress in the liver and thus activate a pathway to degrade ApoB100, a critical protein component of VLDL and LDL, resulting in reduced hepatic output of VLDL-triglycerides. However, it should be considered that there have been a number of other mechanisms proposed for this effect, e.g. increased beta-oxidation, decreased lipogenesis, up/down-regulation of a number of proteins involved in VLDL synthesis. To date, it is not clear what contribution the individual mechanisms make tothe overall reduction in VLDL-triglycerides.
There are some concerns with the mechanistic work presented:
rodent models were used that have very different lipoprotein profile compared with humans.
in rodent hepatocytes PPAR-alpha is highly expressed and this relates to the majority of mechanisms associated with reduced VLDL.
the concentrations of PUFA and vitamin E used were highly unphysiological; they cannot be reached even with high-dose supplements. It would be necessary to repeat these experiments with human cells using lower PUFA and vitamin E concentrations.
The accompanying editorial by RM Krauss raises an important issue that in the MRC/BHF Heart Protection Study in subjects with preexisting CVD or diabetes, triglycerides, cholesterol and ApoB were slightly increased in response to a combination of vitamin E, C and beta-carotene supplements. However, the change in plasma lipids did not result in any significant changes in clinical outcomes, the only relevant criterion to draw a conclusion. In contrast, in the ASAP study HDL ("good cholesterol") was significantly increased in men with vitamin C and there was a trend for increased HDL with vitamin E. Other large intervention studies such as CHAOS and GISSI did not report a significant change of plasma lipids in response to vitamin E. Therefore, extrapolating data from in vitro studies to the situation in the human, and, accordingly, recommendations to the public, should only be made with great caution. Moreover, it is well accepted that n-3-PUFA (EPA/DHA) supplementation in humans decrease plasma triglycerides as expected form Pan et al, but at the same time an overall trend for increased LDL is observed. Also the health effects of the Mediterranean style diet question the applicability of the results of the present study to humans. Mediterranean style diet is rich in PUFA and antioxidants and proven to lower CVD risk.
Thus the study and the accompanying editorial do not justify a premature conclusion such as to "hold the antioxidants and improve plasma lipids?" Further studies are needed to elucidate if antioxidants are critical in hepatic lipid metabolism and if this is meaningful for clinical outcomes.