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, 8 (5), 447-458

Endogenously Increased n-3 PUFA Levels in fat-1 Transgenic Mice Do Not Protect From Non-Alcoholic Steatohepatitis

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Endogenously Increased n-3 PUFA Levels in fat-1 Transgenic Mice Do Not Protect From Non-Alcoholic Steatohepatitis

Marie Liebig et al. Hepatobiliary Surg Nutr.

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Possible reasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6 polyunsaturated fatty acids (n-6 PUFAs) and low consumption of healthy n-3 PUFAs. Due to their anti-inflammatory properties, n-3 PUFAs may have the potential to alleviate chronic liver disease. Herein, we examined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressive NASH.

Methods: Disease was induced in mice by streptozotocin and high fat diet (STZ/HFD) resulting in NASH. NAFLD in 6 and 8 weeks old wild type and fat-1 transgenic STZ/HFD treated mice was analyzed. Unlike all other mammals, fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase, which converts n-6 to n-3 PUFAs, leading to increased n-3 and decreased n-6 PUFA tissue contents.

Results: Liver damage, NAFLD activity score (NAS), hepatic lipid accumulation and inflammation were significantly reduced in fat-1 transgenic STZ/HFD treated mice in the early (6 weeks) but not late (8 weeks) phase of NASH. Simultaneously, mRNA expression of genes involved in fatty acid uptake and storage (Cd36 and Plin3, respectively) was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenic STZ/HFD treated mice.

Conclusions: Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onset of STZ/HFD induced NASH but failed to efficiently protect from NASH development.

Keywords: Non-alcoholic fatty liver disease (NAFLD); fat-1; n-6/n-3; non-alcoholic steatohepatitis (NASH); steatosis.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Representative images of livers of 6 and 8 weeks old STZ/HFD treated wt and fat-1 mice (A) and analysis of liver weight/body weight index (B), plasma activity of GLDH (C) and ALT (D) as well as plasma content of triglycerides (E), free fatty acids (F) and total cholesterol (G) of 6 and 8 week old STZ/HFD treated wt and fat-1 mice. Values are presented as mean ± SD. Group differences were tested by t-test within each time point. *P<0.05, **P<0.01, n=7–14.
Figure 2
Figure 2
NAFLD activity score (A) and its subscores for steatosis (B), inflammation (C) and ballooning (D) of 6 and 8 week old STZ/HFD treated wt and fat-1 mice. Values are presented as mean ± SD. Group differences were tested by t-test within each time point. **P<0.01, ***P<0.001, n=10–14 per group.
Figure 3
Figure 3
Quantitative analysis of Oil Red O (A), CAE (B) and F4/80 (C) stained liver sections of 6 and 8 week old STZ/HFD treated wt and fat-1 mice. Values are presented as mean ± SD. Group differences were tested by t-test within each time point. *P<0.05, **P<0.01, n=9–14 per group. (D) Representative photomicrographs of Oil Red O (left panel) and CAE (right panel) stained liver sections of 6 and 8 week old STZ/HFD treated wt and fat-1 mice. The scale bars mark 100 µm (Oil Red O) and 50 µm (CAE), respectively. CAE positive cells are marked by arrowheads.
Figure 4
Figure 4
mRNA expression of Fatp2 (A), Fatp5 (B), Fabp1 (C), Cd36 (D), Pparg (E), Plin2 (F), Plin3 (G) and Plin5 (H) relative to Rps18 in liver tissue of 6 and 8 week old STZ/HFD treated wt and fat-1 mice. Values are presented as mean ± SD. Group differences were tested by t-test within each time point, *P<0.05, **P<0.01. n=5–6 per group.

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