Article

Menhaden Oil Decreases High-Fat Diet-Induced Markers of Hepatic Damage, Steatosis, Inflammation, and Fibrosis in Obese Ldlr(-/-) Mice

School of Biological and Population Health Sciences and the Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Journal of Nutrition (Impact Factor: 4.23). 06/2012; 142(8):1495-503. DOI: 10.3945/jn.112.158865
Source: PubMed

ABSTRACT The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.

0 Followers
 · 
91 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological studies on Greenland Inuits in the 1970s and subsequent human studies have established an inverse relationship between the ingestion of omega-3 fatty acids [C20-22 omega-3 polyunsaturated fatty acids (PUFA)], blood levels of C20-22 omega-3 PUFA and mortality associated with cardiovascular disease [CVD]. C20-22 omega-3 PUFA have pleiotropic effects on cell function and regulate multiple pathways controlling blood lipids, inflammatory factors and cellular events in cardiomyocytes and vascular endothelial cells. The hypolipemic, anti-inflammatory, anti-arrhythmic properties of these fatty acids confer cardioprotection. Accordingly, national heart associations and government agencies have recommended increased consumption of fatty fish or omega-3 PUFA supplements to prevent CVD. In addition to fatty fish, additional sources of omega-3 PUFA are available from plants, algae and yeast. A key question examined in this review is whether non-fish sources of omega-3 PUFA are as effective as fatty fish-derived C20-22 omega-3 PUFA at managing risk factors linked to CVD. We have focused on omega-3 PUFA metabolism and the capacity of omega-3 PUFA supplements to regulate key cellular events linked to CVD. The outcome of our analysis reveals that non-fish sources of omega-3 PUFA vary in their capacity to regulate blood levels of C20-22 omega-3 PUFA and CVD risk factors.
    The Journal of Lipid Research 08/2012; 53(12). DOI:10.1194/jlr.R027904 · 4.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated hepatic expression of fatty acid elongase-5 (Elovl5) induces FoxO1 phosphorylation, lowers FoxO1 nuclear content and suppresses expression of genes involved in gluconeogenesis. In this report we define the molecular and metabolic basis of Elovl5 control of FoxO1 phosphorylation. Adenoviral-mediated (Ad-Elovl5) induction of hepatic Elovl5 in diet induced obese-glucose intolerant mice and HepG2 cells increased the phosphorylation of Akt2-S473 (mTORC2 site), but not Akt2-T308 (PDK1 site). The Akt2 inhibitor, Akti1/2, blocked Elovl5 induction of FoxO1-S256 phosphorylation in HepG2 cells. Elevated Elovl5 activity in liver and HepG2 cells induced rictor mRNA, rictor protein and rictor-mTOR interaction, while rictor knockdown (siRNA) attenuated Elovl5 induction of Akt2-S473 and FoxO1-S256 phosphorylation in HepG2 cells. Fatty acid analysis revealed that the abundance of cis-vaccenic acid (18:1,n-7) was increased in livers of obese mice and HepG2 cells following Ad-Elovl5 infection. Treating HepG2 cells with Elovl5 substrates established that palmitoleic acid (16:1,n-7), but not gamma-linolenic acid (18:3,n-6), induced rictor protein, Akt-S473 and FoxO1-S256 phosphorylation. Inhibition of fatty acid elongation blocked 16:1,n-7, but not 18:1,n-7, induction of rictor protein and Akt-S473 and FoxO1-S256 phosphorylation. These results establish a novel link between Elovl5 mediated synthesis of 18:1,n-7 and gluconeogenesis through the control of the mTORC2-Akt-FoxO1 pathway.
    The Journal of Lipid Research 10/2012; DOI:10.1194/jlr.M028787 · 4.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical and experimental evidence suggests that obesity-associated inflammation increases disease activity during colitis, attributed in part to the effects of Th17 cells. Using a model of concurrent obesity and colitis, we monitored changes in critical immune cell subsets and inflammatory biomarker expression in three key tissues: visceral adipose tissue, colon (local inflammatory site) and spleen (systemic inflammatory site), and we hypothesized that n-3 PUFA would reduce the percentage of inflammatory immune cell subsets and suppress inflammatory gene expression, thereby improving the disease phenotype. Obesity was induced in C57BL/6 mice by feeding a high fat (HF) diet (59.2% kcal) alone or an isocaloric HF diet supplemented with fish oil (HF-FO) for 12 weeks. Colitis was induced via a 2.5% trinitrobenzene sulfonic acid (TNBS) enema. The HF-FO diet improved the obese phenotype by reducing i) serum hormone concentrations (leptin and resistin), ii) adipose tissue mRNA expression of inflammatory cytokines (MCP-1, IFNγ, IL-6, IL17F and IL-21) and iii) total (F4/80(+) CD11b(+)) and inflammatory adipose tissue M1 (F4/80(+) CD11c(+)) macrophage content compared to HF (P<0.05). In addition, the HF-FO diet reduced both colitis-associated disease severity and colonic mRNA expression of the Th17 cell master transcription factor (RORγτ) and critical cytokines (IL-6, IL-17A, IL-17F, IL-21, IL-23 and IFNγ) versus HF (P<0.05). Compared to HF, the percentage of both splenic Th17 and Th1 cells were reduced by the HF-FO group (P<0.05). Under ex vivo polarizing conditions, the percentage of HF-FO derived CD4(+) T cells that reached Th17 cell effector status was suppressed (P = 0.05). Collectively, these results indicate that n-3 PUFA suppress Th1/Th17 cells and inflammatory macrophage subsets and reconfigure the inflammatory gene expression profile in diverse tissue sites in obese mice following the induction of colitis.
    PLoS ONE 11/2012; 7(11):e49739. DOI:10.1371/journal.pone.0049739 · 3.23 Impact Factor
Show more