Increased dnl and pnpla3 expression by liquid fructose are essential in the production of fatty liver and hypertriglyceridemia in a non-obese hfd-fed rat model

Background and Aims : To delineate the contribution of saturated fatty acids (FA) of dietary origin vs DNL to fatty liver and hypertriglyceridemia development.Methods: 24 female rats were randomly assigned to 3 groups (n=8 each) and maintained for 3 months in: (1) standard rodent chow (control, CT); (2) High-fat diet (rich in palmitic and stearic FA, HFD) and (3) HFD with 10% w/v fructose in drinking water (HFHFr). Zoometric parameters, plasma biochemistry, and liver ORO stain, lipidomics and expression of proteins involved in FA metabolism were analyzed at the end of the treatment.Results: Both dietary interventions increased the calories ingested without modifying body weight. HFD increase in liver TGs (x1.8 vs CT), was further enhanced in HFHFr livers (x11.0 vs CT), and accompanied by hypertriglyceridemia (x1.7 vs CT/HFD) and reduced liver FA β-oxidation (x0.7 vs CT). TGs of HFHFr livers showed increased concentrations of several FA (palmitic x6.3, stearic x13.9, oleic x17.6, and palmitoleic acid x39.2 vs CT). While HFD livers showed a higher content of ceramides, HFHFr samples showed unchanged ceramides, and an increase in diacylglycerols. Only the HFHFr diet led to a marked increase in the expression of enzymes and proteins involved in FA synthesis and TG metabolism, such as ChREBPβ, a transcription factor that regulates DNL, and PNPLA3, a lipase that mobilizes TGs stored in lipid droplets for VLDL formation and secretion.Conclusions: Fructose, increasing DNL and PNAPLA3 expression, and reducing FA catabolism, is determinant in the production of liver steatosis and hypertriglyceridemia. Background and Aims : To delineate the contribution of saturated fatty acids (FA) of dietary origin vs DNL to fatty liver and hypertriglyceridemia development. Methods: 24 female rats were randomly assigned to 3 groups (n=8 each) and maintained for 3 months in: (1) standard rodent chow (control, CT); (2) High-fat diet (rich in palmitic and stearic FA, HFD) and (3) HFD with 10% w/v fructose in drinking water (HFHFr). Zoometric parameters, plasma biochemistry, and liver ORO stain, lipidomics and expression of proteins involved in FA metabolism were analyzed at the end of the treatment. Results: Both dietary interventions increased the calories ingested without modifying body weight. HFD increase in liver TGs (x1.8 vs CT), was further enhanced in HFHFr livers (x11.0 vs CT), and accompanied by hypertriglyceridemia (x1.7 vs CT/HFD) and reduced liver FA β-oxidation (x0.7 vs CT). TGs of HFHFr livers showed increased concentrations of several FA (palmitic x6.3, stearic x13.9, oleic x17.6, and palmitoleic acid x39.2 vs CT). While HFD livers showed a higher content of ceramides, HFHFr samples showed unchanged ceramides, and an increase in diacylglycerols. Only the HFHFr diet led to a marked increase in the expression of enzymes and proteins involved in FA synthesis and TG metabolism, such as ChREBPβ, a transcription factor that regulates DNL, and PNPLA3, a lipase that mobilizes TGs stored in lipid droplets for VLDL formation and secretion. Conclusions: Fructose, increasing DNL and PNAPLA3 expression, and reducing FA catabolism, is determinant in the production of liver steatosis and hypertriglyceridemia.