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

• Published in: Journal of hepatology 2012-04, Vol.56 (4), p.900-907
• Main Authors: Li, Jiong, Huang, Jin, Li, Jian-Shuang, Chen, Hong, Huang, Kun, Zheng, Ling
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cohort Effect; Diet, High-Fat - adverse effects; Dietary Fats - pharmacology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - physiology; Epigenesis, Genetic - physiology; ER stress; Fatty Liver - epidemiology; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Histone methylation; Histones - metabolism; Lipogenesis; Lipogenesis - drug effects; Lipogenesis - physiology; Liver - physiopathology; Male; Maternal obesity; Medical sciences; Metabolic diseases; Methylation; Mice; Models, Animal; NAFLD; Non-alcoholic Fatty Liver Disease; Obesity; Obesity - epidemiology; Risk Factors; Stress, Physiological - drug effects; Stress, Physiological - physiology; Time Factors
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2011.10.018

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 LXRα, ERO1-α, histone methylations, and H3K9 histone methyltransferase. Furthermore, chromatin immunoprecipitation (CHIP) assay demonstrated a significantly reduced accumulation of methylated histones in LXRα and ERO1-α 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.