The World Health Organisation (WHO) defines being overweight or obese as “abnormal or excessive fat accumulation that presents a risk to health.”

In 2024, obesity is a major global health problem. The Non-Communicable Diseases Risk Factor Collaboration (NCD-RisC) recently published findings that estimate that more than one billion people in the world are now living with obesity. More specifically, this equates to nearly 880 million adults, 159 million children, and adolescents aged 5–19 years.

A high-fat diet and elevated fat intake associated with obesity can result in fat accumulation in the liver. Moreover, the buildup of fats in the liver over time, which can also be referred to as non-alcoholic fatty liver disease (NAFLD), causes an increased risk of serious health conditions such as liver damage, liver cancer, heart disease, stroke, type 2 diabetes, kidney disease, and colorectal cancer. Research regarding the treatment of NAFLD has mostly focused on fat metabolism inside the liver.

However, researchers from Japan have recently published novel research in the Open Access journal Nutrients, which shows how gut hormones affect lipid accumulation in the liver. This research aims to highlight an alternative treatment pathway to prevent lipid buildup in the liver to prevent and improve NAFLD.

Here, we explore their research and its potential in future NAFLD therapies.

Liver functions in the body

The liver has a variety of important roles in the body; its main function is to regulate chemical levels in the blood. Blood travels through the liver from the stomach and intestines, where it is processed. This includes:

• Absorbing nutrients from the diet and converting them into fuel for the body, as well as storing these substances and making them available for when the body needs them.
• Filtering toxins and bacteria from the body and converting them into harmless substances or ensuring they are released from the body.
• Regulating the levels of fats, amino acids, and glucose in the blood.
• Regulating blood clotting, processing haemoglobin, storage of iron, and production of proteins for blood plasma.
• Clearance of bilirubin, a byproduct of red blood cells.
• Conversion of ammonia, a poisonous waste product of bacteria in the intestines, to urea.
• Production of cholesterol and transport proteins for fats.
• Production of bile, which transports waste and breaks down fats in the small intestine during digestion.
• Regulation and metabolism of endocrine and steroid hormones such as thyroid hormones, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2).

Hormonal control of lipid regulation in the liver

GLP-1, GLP-2, and glucagon are proglucagon-derived peptides (PDGPs). The molecules help to regulate lipid metabolism in the liver, adipocytes, and intestines and are all derived from the same precursor, proglucagon.

Glucagon’s role in the liver

“Pancreatic α-cells secrete glucagon, a hormone that increases glucose production by promoting glycogenolysis, gluconeogenesis, and amino acid catabolism in the liver. Additionally, studies show that glucagon plays a role in liver lipid metabolism by promoting lipolysis in adipocytes and fatty acid oxidation in the liver in vitro

Lipolysis is a metabolic process that takes place in adipose cells, where triglycerides are broken down into glycerol and fatty acids. These biproducts are then transported to the liver and broken down into energy.

Adipose tissue (AT) works together with the liver to regulate energy homeostasis in the body. AT can store energy when the body has been fed and release it in the fasting state. However, in cases/state of obesity, excess nutrients are stored in AT. This results in insufficient storage availability for other lipids usually stored in the AT, such as the free fatty acids (FFA). Because of this, FFAs are distributed to other organs and stored as ectopic fats and produce reactive oxidative species, resulting in inflammation. Moreover, because lipids are not processed and stored correctly due to excess intake, they are stored in the liver. This causes excess fat accumulation and increases the risk of developing a serious health condition.

The full role of glucagon in the beneficial effects on lipid metabolism is not understood. Additionally, GLP-1 and GLP-2 have been associated with hepatic lipid accumulation. Because of this, the researchers from Japan used mouse models to investigate the PDGP’s effects on adipose tissue and lipid metabolism in the liver.

“If we can examine in more detail how PGDPs specifically regulate lipid absorption in the gut, we hope to clarify the relationship between diet, hormones, and intestinal bacteria sufficiently to recommend a diet that is less conducive to obesity and fatty liver disease.” – Dr Yusuke Seino, author on paper.

Analysing PDGP’s effect on lipid metabolism in mice

The researchers fed mice deficient in PGDP and healthy  mice high-fat diets for 7 days. They then analysed the mice for differences in lipid metabolism in the liver, adipose tissue, and duodenum.

This involved analysing the PGPD-deficient and control mice’s blood glucose, hormone, and triglyceride levels. Additionally, they performed an oral fat tolerance, which measures the body’s response to a high-fat meal. Furthermore, they also performed an intraperitoneal fat tolerance test, which measures how well an animal’s body metabolises lipids. Other analyses involved the isolation of RNA and quantitative polymerase chain reaction analysis of tissues, including the livers, adipose tissues, and intestinal tracts.

The researchers stained the liver, adipose tissue and duodenum of both mice using immunohistochemistry methods to compare any differences. Furthermore, the researchers measured hepatic triglyceride, FFA, total cholesterol, and glycogen in faecal samples. Furthermore, the faecal samples were analysed using methods such as DNA sequencing and Quantitative PCR, where analysis of gut microbes was then performed.

“When we subjected both GCGKO mice and control mice to an HFD for one week, the GCGKO mice exhibited a significantly lower increase in hepatic free fatty acid (FFA) and triglyceride levels, along with reduced adipose tissue weight.” – Dr Yusuke Seino.

Future implications for fatty liver disease

The researchers identified that mice deficient in PGPD demonstrated less of an increase in adipose tissue weight, plasma FFA and hepatic triglycerides, and FFA content following a high-fat diet in comparison to the control mice.

They hypothesised that this was due to decreased lipid absorption from the intestinal tract. Additionally, their genetic analysis showed that deficient mice had a decreased expression of the genes CD36 and PPARα. CD36 plays a major role in the liver’s hepatic FFA uptake. PPARα is the master regulator of hepatic lipid metabolism during fasting.

The authors conclude that decreased expression of CD36 and PPARα may contribute to the reduced lipid absorption in deficient mice.

“In the future, oral dual antagonists of GLP-2 and glucagon could emerge as potential therapies for obesity and fatty liver, especially given their roles in insulin sensitivity and lipid metabolism.” – Dr Yusuke Seino.

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