The global rise in fatty liver disease, primarily fuelled by high-fat diets and obesity, presents a significant and growing health challenge. Characterised by the excessive storage of fats in the liver, this condition increases the risk of various metabolic disorders and underscores the complex interplay between diet and liver health. Although traditional research has predominantly focused on understanding fat metabolism directly within the liver, recent studies have begun to highlight the pivotal influence of the gut in this multifaceted process. Among the key players in this interaction are proglucagon-derived peptides (PGDPs) such as glucagon, GLP-1, and GLP-2. These hormones, all derived from the proglucagon molecule, have been shown in previous studies to influence lipid accumulation in the liver indirectly. However, how they contribute to liver fat accumulation remains largely unclear.
In a groundbreaking study led by Associate Professor Yusuke Seino of Fujita Health University, published on 14 July 2024 in the journal Nutrients, new light has been shed on the role of PGDPs in regulating fat absorption and subsequent liver fat buildup. The research team, including Mr Koki Nishida, Mr Atsushi Suzuki, and Mr Yoshiki Hirooka from Fujita Health University, as well as Mr Yoshikata Hayashi from Nagoya University, employed genetically modified mice lacking PGDPs (GCGKO mice) to explore their response to a high-fat diet over seven days, aiming to uncover new preventative strategies for fatty liver.
The findings were revealing. “When both GCGKO mice and control mice were subjected to a high-fat diet for one week, the GCGKO mice demonstrated a significantly lower increase in hepatic free fatty acid and triglyceride levels, as well as reduced adipose tissue weight,” explained Dr Seino. This reduction in lipid accumulation was linked to decreased lipid absorption through the CD36 pathway in the intestinal tract despite the mice’s reduced liver fat-burning (β-oxidation) capacity.
Furthermore, the research identified a decrease in the expression levels of genes associated with free fatty acid oxidation in the high-fat diet-fed GCGKO mice. Notably, the duodenum’s mRNA levels of Pparα (peroxisome proliferator receptor alpha) and Cd36 (cluster of differentiation 36) were lowered, correlating with diminished fat uptake in the intestines and increased faecal cholesterol content. This indicates that the absence of PGDPs prevents diet-induced fatty liver primarily by reducing intestinal fat absorption.
Interestingly, the study also pointed to lower plasma triglyceride levels during the oral fat tolerance test in HFD-fed GCGKO mice, further substantiating the reduced lipid absorption. Moreover, the research underscored a complex relationship between diet, hormonal responses, and intestinal microbiota. Notable shifts in gut bacteria were observed in HFD-fed GCGKO mice, with increases in Parabacteroides and decreases in Lactobacillus, which are associated with resistance to obesity. These microbial changes highlight the potential of dietary and hormonal interventions to enhance gut health and metabolic functions.
Expanding on the implications of their findings, Dr Seino suggested, “A more detailed examination of how PGDPs specifically regulate lipid absorption in the gut could clarify the relationship between diet, hormones, and intestinal bacteria to a degree that allows us to recommend a diet that is less conducive to obesity and fatty liver disease.” Looking to the future, he added, “Oral dual antagonists of GLP-2 and glucagon could potentially become effective therapies for obesity and fatty liver, particularly due to their roles in insulin sensitivity and lipid metabolism.”
In conclusion, these findings open the door to the development of targeted therapies designed to tackle this prevalent health issue, potentially improving the health outcomes for millions of individuals globally affected by fatty liver disease. This study enhances our understanding of the biochemical pathways involved and sets the stage for innovative treatments that could revolutionise the management of fatty liver disease.
More information: Koki Nishida et al, Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides, Nutrients. DOI: 10.3390/nu16142270
Journal information: Nutrients Provided by Fujita Health University
