Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets

Background & Aims: The dramatic rise of nonalcoholic fatty liver disease (NAFLD) among children in the past decade cannot be solely explained by the increased high fat diet (HFD) intake in kids. Recent studies suggest that the offspring of HFD-fed mothers develop a worse form of NAFLD when weaned on the HFD than when weaned on the normal chow (NC), indicating that a feed-forward circle may exacerbate the syndromes throughout multiple generations. In the present study, the aforementioned feed-forward circle was investigated in mice by employing continuous HFD feeding for three generations. Methods: C57BL/6 mice were fed with either a HFD or NC for three consecutive generations (F0, F1, and F2). Body weight, food intake, hepatic histology; levels of insulin, leptin, and triglycerides; expression of factors involved in lipogenesis and endoplasmic reticulum (ER) stress pathways; and histone methylation status were investigated in male offspring. Results: Obesity occurred earlier, became more severe through generations (F2 >F1 >F0), and was accompanied by a gradual increase of histological scoring of steatosis in male mice with transgenerational HFD feeding. The highest degree of steatosis occurred in HFD-treated F2 mice and was associated with the highest levels of insulin and leptin. The latter mice were characterized by enhanced lipogenesis and ER stress with a trend of transgenerational changes was detected for LXR alpha, ERO1-alpha, histone methylations, and H3K9 histone methyltransferase. Furthermore, chromatin immunoprecipitation (CHIP) assay demonstrated a significantly reduced accumulation of methylated histones in LXR alpha and ERO1-alpha gene promoters. Conclusions: Under HFD feeding stress, the male offspring of the F2 generation (derived from both grand-maternal and maternal obesity) are extremely susceptible to developing obesity and hepatic steatosis. This is presumably a consequence of transgenerational accumulation of epigenetic modifications leading to up-regulation of lipogenesis and ER stress pathways in the liver. (c) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.