Final Report Summary - GLAPI (Gut-liver axis’ protein impact: Influence of dietary protein on gene expression and metabolic phenotype in the gut-liver axis)
The objective of this project was to detect mechanisms by which a HP diet affects hepatic lipid accumulation and obesity. Moreover we aimed to study the effect of HP on the intestinal mucosa and the microbiota. Additionally, we linked the experiments in rodents to a clinical study that is currently performed in an accompanying project.
To investigate the acute and long term effect of high protein ingestion on hepatic lipid accumulation and body fat under both low and high fat (HF) conditions, mice were fed combinations of high (35 energy%) or low (10 energy%) fat and high (50energy%) or normal (15 energy%) protein diets for 1 or 12 weeks. The analyses include gene expression and metabolic phenotyping in the gut mucosa and liver, characterization of the microbiota, gut, liver and peripheral inflammatory state, hepatic lipogenesis and steatosis, body composition and food intake behavior.
Food intake was not affected by the different diets. However, mice fed the HP diets displayed a lower body weight, developed less adiposity and decreased hepatic lipid accumulation, which could be attributed to a combination of several processes. Next to an increased hepatic VLDL production rate, increased energy utilization due to enhanced protein catabolic processes, such as transamination, TCA cycle and oxidative phosphorylation was found upon high protein ingestion. Mostly comparable effects were observed in humans; effect sizes were however much more subtle. Analysis of the signalling effect of selected dietary amino acids on the liver are still on going.
With respect to the intestine, preliminary analysis of the small intestinal gene expression data also suggested enhanced protein catabolism, and suppression / delay of lipid uptake and metabolism. However, effects of increased dietary protein on gene expression were only modest compared to those of increased dietary fat. Moreover, the morphology, villus-length and crypt depth, and cell proliferation in the small intestine was not affected by increased dietary protein, in contrast to increased dietary fat. Analyses of the microbiome composition of the distal small intestine revealed no significant changes, despite an increased concentration of branched-chain short-chain fatty acids that are markers for increased protein fermentation.
Taken together, it was demonstrated that feeding a HP diet prevented the development of adiposity and NAFLD in mice by enhancing lipid secretion into VLDL particles and a less efficient use of ingested calories. Understanding the underlying molecular mechanisms of these effects will further contribute evidence-based dietary advice in the combat against obesity and the metabolic syndrome.