Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice

Received 16 September 2009; received in revised form 18 January 2010; accepted 26 February 2010. published online 22 April 2010.

Background & Aims

Excessive trans-fatty acids (TFA) consumption has been thought to be a risk factor mainly for coronary artery diseases while less attention has been paid to liver disease. We aimed to clarify the impact of TFA-rich oil consumption on the hepatic pathophysiology compared to natural oil.

Methods

Mice were fed either a low-fat (LF) or high-fat (HF) diet made of either natural oil as control (LF-C or HF-C) or partially hydrogenated oil, TFA-rich oil (LF-T or HF-T) for 24weeks. We evaluated the liver and body weight, serological features, liver lipid content and composition, liver histology and hepatic lipid metabolism-related gene expression profile. In addition, primary cultures of mice Kupffer cells (KCs) were evaluated for cytokine secretion and phagocytotic ability after incubation in cis- or trans-fatty acid-containing medium.

Results

The HF-T-fed mice showed significant increases of the liver and body weights, plasma alanine-aminotransferase, free fatty acid and hepatic triglyceride content compared to the HF-C group, whereas the LF-T group did not differ from the LF-C group. HF-T-fed mice developed severe steatosis, along with increased lipogenic gene expression and hepatic TFA accumulation. KCs showed increased tumor necrosis factor secretion and attenuated phagocytotic ability in the TFA-containing medium compared to its cis-isomer.

Conclusions

Excessive consumption of the TFA-rich oil up-regulated the lipogenic gene expression along with marked hepatic lipid accumulation. TFA might be pathogenic through causing severe steatosis and modulating the function of KCs. The quantity and composition of dietary lipids could be responsible for the pathogenesis of non-alcoholic steatohepatitis.

Abbreviations: NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, FFA, free fatty acid, LPS, lipopolysaccharide, TFA, trans-fatty acid, ALT, alanine-aminotransferase, LF(-C or -T), low-fat (control or TFA-rich) diet, HF(-C or -T), high-fat (control or TFA-rich) diet, KCs, Kupffer cells (KCs), AST, aspartate-aminotransferase, TG, triglyceride, ELISA, Enzyme-Linked ImmunoSorbent Assay, HDL, high density lipoprotein, (V)LDL, (very) low density lipoprotein, NAS, NAFLD activity score, TBARS, thiobarbituric acid reactive substances, TNFα, tumor necrosis factor α, IL-6, interleukin-6, SD, standard deviation, iNOS, inducible nitric oxide synthase, TGF-β, transforming growth factor-β, SREBP-1, sterol regulatory element-binding protein-1, FAS, fatty acid synthase, ACC, acetyl CoA carboxylase, PPAR, peroxisome proliferator activated receptor, PGC-1β, PPARγ coactivator-1β, PUFA, polyunsaturated fatty acid, MUFA, monounsaturated fatty acid, SFA, saturated fatty acid

Keywords: trans-Fatty acid, NASH, NAFLD, Metabolic syndrome, Kupffer cell

1 Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574, Japan

2 Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, Sendai, Japan

3 Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

4 Department of Pathology, Tohoku University Hospital, Sendai, Japan

Corresponding author. Tel.: +81 22 717 7171; fax: +81 22 717 7177.

PII: S0168-8278(10)00270-9

doi:10.1016/j.jhep.2010.02.029

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