Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation.
OBJECTIVE
Non-alcoholic fatty liver disease is the result of an imbalance in hepatic lipid partitioning that favors fatty acid synthesis and storage over fatty acid oxidation and triglyceride secretion. The progressive, inflammatory disorder of steatohepatitis can be prevented or reversed by correcting this lipid imbalance by activating peroxisome proliferator-activated receptor (PPAR) alpha, a transcription factor which regulates fatty acid oxidation. n-3 polyunsaturated fatty acids (PUFA), such as those found in fish oil (FO), are naturally occurring PPARalpha ligands which also suppress lipid synthesis.


METHODS
We tested the role of dietary activation of PPARalpha by feeding mice a n-3 PUFA-enriched FO diet in the methionine and choline deficient (MCD) model of steatohepatitis. Results were compared with mice fed the corresponding diet supplemented with monounsaturated fatty acids as olive oil (OO).


RESULTS
As expected, FO feeding led to robust hepatic PPARalpha activation in control mice, and decreased expression of genes involved with fatty acid synthesis. Such lipolytic gene expression profile was also clearly evident in FO MCD-fed mice, and was associated with reduced hepatic lipid accumulation in comparison with mice fed OO MCD diet. FO feeding in control mice also caused marked hepatic accumulation of lipoperoxides compared with OO and chow-fed mice. This was further exacerbated in FO MCD-fed animals, which developed steatohepatitis characterized by mild steatosis and moderate inflammation in comparison with OO MCD-fed mice; such inflammatory recruitment was not related to NF-kappaB activation or enhanced cyclooxygenase-2 activity.


CONCLUSIONS
Feeding an n-3 PUFA-enriched diet activated PPARalpha and suppressed hepatic de novo lipogenesis, but failed to prevent development of steatohepatitis in the presence of methionine and choline deficiency. Instead, the very high levels of hepatic lipoperoxides may have abrogated the protection that would otherwise be conferred by PPARalpha activation, and could also be responsible for lipotoxic hepatocellular injury and inflammatory recruitment.
Larter
Claire Z
CZ
Australian National University Medical School at The Canberra Hospital, Canberra, Australian Capital Territory, Australia. claire.larter@anu.edu.au
Yeh
Matthew M
MM
Cheng
Jenny
J
Williams
Jacqueline
J
Brown
Sandie
S
dela Pena
Aileen
A
Bell-Anderson
Kim S
KS
Farrell
Geoffrey C
GC
D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005227:Fatty Acids / Q000096:biosynthesis; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism*; D050155:Lipogenesis / Q000187:drug effects; D008066:Lipolysis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism*
D004042:Dietary Fats, Unsaturated; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D008054:Lipid Peroxides; D047493:PPAR alpha; D008715:Methionine