Fatty liver disease, which involves an excessive buildup of fat in the liver, is becoming a serious health issue globally. Proglucagon-derived peptides (PGDPs) such as glucagon, GLP-1, and GLP-2 play a crucial role in managing lipid metabolism in the liver, yet the exact mechanisms at play remain unclear. Recent research from Fujita Health University has delved into how PGDPs influence fat accumulation in the liver by studying GCGKO mice that lack these peptides.
The buildup of fat in the liver is largely influenced by high-fat diets and obesity, making it an increasingly common health challenge worldwide. This condition, marked by large amounts of fat in the liver, can lead to serious metabolic issues. While fair share of studies has centered on the liver’s own fat metabolism, recent insights shed light on the significant role that the gut plays in this complex interplay. Proglucagon-derived peptides (PGDPs) are recognized as essential hormones regulating liver lipid metabolism. Since they are derived from the proglucagon precursor, previous research has indicated that GLP-1 and GLP-2 may indirectly contribute to liver fat accumulation. However, their exact roles in this context still need clarification.
A recent study conducted by Associate Professor Yusuke Seino and his team from Fujita Health University, published in Nutrients on July 14, 2024, investigates how PGDPs influence fat absorption and the accumulation of fat in the liver. The research team, including Mr. Koki Nishida, Mr. Atsushi Suzuki, Mr. Yoshiki Hirooka from Fujita Health University, and Mr. Yoshikata Hayashi from Nagoya University, used genetically modified mice (GCGKO mice) that lack PGDPs to explore their response to a high-fat diet (HFD) over a week, revealing potential new methods to fight fatty liver.
According to Dr. Seino, “When we exposed both GCGKO and control mice to an HFD for a week, we observed that GCGKO mice showed a significantly lesser rise in hepatic free fatty acid (FFA) and triglyceride levels, along with a reduction in adipose tissue weight.” These results were linked to a decline in lipid absorption via the CD36 pathway in the gut, even with a diminished capacity for fat burning (β-oxidation) in the liver.
The findings also showed that HFD-fed GCGKO mice had lower levels of genes associated with FFA oxidation. Notably, the mRNA levels of Pparα (peroxisome proliferator-activated receptor alpha) and Cd36 (cluster of differentiation 36) were decreased in the duodenum, which corresponded with lower fat uptake in the intestines and increased fecal cholesterol levels. This indicates that the absence of PGDPs helps to avert diet-induced fatty liver by reducing fat absorption in the gut.
Interestingly, although the liver fat-burning function was reduced, the primary mechanism preventing fat accumulation appears to be a decline in fat absorption from the intestines. Additionally, HFD-fed GCGKO mice exhibited lower plasma triglyceride levels during oral fat tolerance tests (OFTT), further supporting the notion of diminished lipid absorption.
The study also highlights the complex relationship among diet, hormonal reactions, and intestinal bacteria. HFD-fed GCGKO mice exhibited significant alterations in gut microbiota, including an increase in Parabacteroides and a decrease in Lactobacillus, both associated with obesity resistance. These findings suggest the potential for dietary and hormonal strategies to improve gut health and metabolic functions.
Dr. Seino added, “By diving deeper into how PGDPs specifically govern lipid absorption in the intestines, we aim to better understand the interplay between diet, hormones, and gut bacteria to recommend a diet that could help reduce the risk of obesity and fatty liver disease.”
Regarding long-term prospects, Dr. Seino mentioned, “In the future, oral dual antagonists of GLP-2 and glucagon may serve as promising treatments for obesity and fatty liver, particularly considering their influencing roles on insulin sensitivity and lipid metabolism.”
In conclusion, these discoveries could contribute to the development of targeted treatments aimed at addressing this growing health crisis, which could enhance the well-being of millions affected by fatty liver disease globally.
