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Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation.
J Gastroenterol Hepatol. 2008 Feb; 23(2):267-75.JG

Abstract

BACKGROUND AND AIM

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.

Authors+Show Affiliations

Australian National University Medical School at The Canberra Hospital, Canberra, Australian Capital Territory, Australia. claire.larter@anu.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17868330

Citation

Larter, Claire Z., et al. "Activation of Peroxisome Proliferator-activated Receptor Alpha By Dietary Fish Oil Attenuates Steatosis, but Does Not Prevent Experimental Steatohepatitis Because of Hepatic Lipoperoxide Accumulation." Journal of Gastroenterology and Hepatology, vol. 23, no. 2, 2008, pp. 267-75.
Larter CZ, Yeh MM, Cheng J, et al. Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. J Gastroenterol Hepatol. 2008;23(2):267-75.
Larter, C. Z., Yeh, M. M., Cheng, J., Williams, J., Brown, S., dela Pena, A., Bell-Anderson, K. S., & Farrell, G. C. (2008). Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. Journal of Gastroenterology and Hepatology, 23(2), 267-75.
Larter CZ, et al. Activation of Peroxisome Proliferator-activated Receptor Alpha By Dietary Fish Oil Attenuates Steatosis, but Does Not Prevent Experimental Steatohepatitis Because of Hepatic Lipoperoxide Accumulation. J Gastroenterol Hepatol. 2008;23(2):267-75. PubMed PMID: 17868330.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. AU - Larter,Claire Z, AU - Yeh,Matthew M, AU - Cheng,Jenny, AU - Williams,Jacqueline, AU - Brown,Sandie, AU - dela Pena,Aileen, AU - Bell-Anderson,Kim S, AU - Farrell,Geoffrey C, Y1 - 2007/09/12/ PY - 2007/9/18/pubmed PY - 2008/4/4/medline PY - 2007/9/18/entrez SP - 267 EP - 75 JF - Journal of gastroenterology and hepatology JO - J. Gastroenterol. Hepatol. VL - 23 IS - 2 N2 - BACKGROUND AND AIM: 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. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/17868330/Activation_of_peroxisome_proliferator_activated_receptor_alpha_by_dietary_fish_oil_attenuates_steatosis_but_does_not_prevent_experimental_steatohepatitis_because_of_hepatic_lipoperoxide_accumulation_ L2 - https://doi.org/10.1111/j.1440-1746.2007.05157.x DB - PRIME DP - Unbound Medicine ER -