Study On The Relationship Of Endoplasmic Reticulum Stress And Insulin Resistance With The Development Of Goose Fatty Liver

The prevalence of nonalcoholic fatty liver disease (NAFLD) constitutes a great threat to human health. With the enhancement of research activity in this field, many great progresses have been made in understanding the mechanisms underlying the development of NAFLD in human and other mammalian animals. Recent studies in mammals indicate endoplasmic reticulum stress (ERS) plays an important role in the occurrence of insulin resistance (IR). IR may induce hyperinsulinemia that in turn promotes hepatic lipogenesis. However, understanding the mechanism underlying the development of goose fatty liver is very limited. As genetic distance in evolutionary tree is big between geese and mammals with the difference in nutrient metabolism, especially lipid metabolism, it is unclear whether ERS and IR are also the underlying mechanisms for the development of goose fatty liver. In this study, experiments with cells or geese were performed to address this, timely, goose primary hepatocytes were treated with high glucose and fatty acids, the mRNA abundance of ERS marker genes (e.g. Grp78 and Xbp1) were subsequently determined in the cells; and Landes geese were treated with ERS inducers or overfed for 19 days, followed by analysis on blood chemistry, glucose tolerance test (GTT), insulin tolerance test (ITT), gene expression, and biopsy. The major results are as follows:1. Induction of ERS in goose primary hepatocytes by high glucose and palmitate. We treated goose primary hepatocytes with high glucose and palmitate supplemented with or without oleate and linoleate. The mRNA expression of ERS marker genes (e.g. Grp78 and Xbpl) was determined by quantitative PCR. Data indicated that the expression of Grp78/Xbpl genes was induced by high glucose and palmitate in goose primary hepatocytes, and this induction was suppressed by supplemental oleate and linoleate. The findings suggest that, as in mammalian cells, ERS can be induced by high glucose and saturated fatty acids in goose primary hepatocytes, and unsaturated fatty acids suppress this ERS.2. The ERS inducers, tunicamycin and thapsigargin, could induce hepatic ERS, systematic glucose intolerance, and fatty liver in goose.70-day-old geese were treated with the inducers (which mainly act on the liver), and variables associated with ERS or IR were subsequently determined. Quantitative PCR analysis showed that, compared to control group, the expression of Grp78 in the liver was induce by tunicamycin (P<0.01). Moreover, the geese fed with tunicamycin for 20d appeared to be intolerant to blood glucose, and their livers showed the features of hepatic steatosis, suggesting ERS can induce IR and hepatic steatosis in geese. The assay with thapsigargin further supported this notion that ERS may induce IR in goose.3. Overfeeding induced systematic glucose intolerance and fatty liver, but did not induce hepatic ERS in goose.70-day-old geese were overfed and normally fed. We performed GTT at 77 and 84 days of age and determined postprandial blood glucose levels at 85-day-old. Data indicated that, compared to normally fed geese, ERS was not induced in the overfed geese, probably due to the upregulation of fatty acid desaturases. However, the overfed geese were more intolerant to injected glucose after 7 d of overfeeding. At 14 d, this phenomenon was more obvious. Moreover, at 15 d of overfeeding, postprandial blood glucose in the overfed geese was also significantly higher than the control geese without starvation. At 18 d, ITT further supported the notion that overfeeding induced insulin resistance in the development of goose fatty liver. This IR was accompanied with the change of liver color from normal deep red to fatty liver-like khaki color.In summary, endoplasmic reticulum stress can cause insulin resistance and fatty liver in goose. However, overfeeding induced insulin resistance and fatty liver was not ERS-depended. Thus, we conclude that insulin resistance is closely related to goose fatty liver, and IR is an important mechanism underlying the development of goose fatty liver.