Prolonged intake of hyperproteic casein-based diet promotes a molecular environment leading to liver triacylglycerol deposition and increases markers of hepatic damage in rats

Introduction: High protein (HP) diets have been associated to body weight loss and positive metabolic effects on obese subjects. However, controversy exists on the effects of long-term intake of these diets, as more recent reports point to health risk and higher mortality. Liver is a key organ involved in macronutrient handling, thus, we aimed to analyse the effects of HP diets on liver metabolism and health.
Methods: We performed a transcriptome analysis on liver of healthy adult male Wistar rats fed for 4 months with a casein-rich HP diet and analysed adiposity and molecular parameters related to metabolic syndrome and liver injury.
Results: Compared to rats on a control diet, HP-fed animals, that ingested 2.3 times higher amount of protein than controls, showed a lower cumulative food intake and lower body weight; although this lower body weight was not related to decreased adiposity. HP-fed animals presented lower serum cholesterol levels and were apparently healthy according to parameters related to metabolic syndrome: no differences were found in circulating non-esterified fatty acids or triaclyglicerols (TG) in comparison to controls. In liver, long-term intake of the casein-rich diet had an impact on metabolic pathways related with amino acid uptake/metabolism and lipid synthesis, indicative of higher TG deposition. Liver transcriptomic analysis also revealed up-regulation of immune-related genes and changes in expression of genes involved in acid-base maintenance and oxidative stress, pointing to alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. In line with these transcriptomic changes, clear functional signs of unhealthy effects, such increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha) were observed. Moreover, chronic intake of the HP diet produced a dramatic increase of hepatic HSP90, a marker of liver injury.
Conclusion: A drastic and prolonged increase in diet protein intake, resulting in a high acid load, induces a hepatic transcriptome signature reflecting increased TG deposition and increased levels of markers of liver/health injury.