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Understanding the role of little known gene in regulating metabolism

Thousands of genes are involved in the regulation of our day-to-day metabolism and relatively little is understood about their function. One key protein, an ABC Transporter called ABCC5, has recently been predicted to be a susceptibility gene for Type 2 diabetes. In a new study Associate Professor Heidi de Wet of the Department of Physiology, Anatomy and Genetics has confirmed ABCC5's role in energy metabolism and identified the mechanism behind its metabolic impact for the first time.

A multitude of physiological signals regulates our appetite and metabolism. An empty stomach triggers the “hunger hormone”, Ghrelin, which acts on the brain to stimulate feelings of hunger. When the stomach becomes full, those hunger signals are muted. The arrival of digested food in the small intestine from the stomach engages with hormone-secreting cells known as enteroendocrine cells. These cells are the first point of contact between you and your food: the digested food triggers receptors on these endocrine cells causing them to release hormones into the circulatory system. These hormones have very important downstream effects: they regulate the release of insulin from the pancreas, prompt capillaries to move blood towards the stomach to absorb the food, trigger feelings of satiety in the brain, and interacts with the liver, muscle and fat to enable it to absorb glucose. In essence, 'these hormones are spectacularly important because they drive human metabolism in response to food,' explains Professor de Wet.

ATP-binding cassette transporters (ABC transporters) are proteins found in cell membranes that transport various substances in and out of the cell. This family of transporters is very well known in the context of certain diseases. Loss of function mutations in the CFTR gene (ABCC7) can cause the respiratory disease Cystic Fibrosis, while gain of function mutations in the multidrug resistance-associated protein 1 (ABCC1) can cause a tumour to become resistant to chemotherapy. However, the function of one of these transporters, an orphan transporter called ABCC5, was unknown for some time, until a recent study found compelling evidence for its key role in energy metabolism.

A Genome-Wide Association Study used subcutaneous adipose tissue from patients and control subjects stored as part of a diabetes biobank. The study demonstrated that overexpression of ABCC5 in human adipose tissue would cause their subjects to have a three-fold increased risk of developing type 2 diabetes with age. The individuals with increased levels of ABCC5 had increased visceral fat accumulation and were more insulin resistant. Consequently, the study predicted that ABCC5 may be the new susceptibility gene for Type 2 diabetes. However, the mechanism behind this susceptibility was unknown.

In order to confirm the role of ABCC5 in energy metabolism and understand the mechanism behind ABCC5’s metabolic impact, a team led by Associate Professor Heidi de Wet knocked the gene out in mice using a CRISPR technique and examined their metabolic profile. Distinctly opposite to the human overexpression phenotype, mice with no ABCC5 were lean, had less fat and were more active. They also demonstrated increased insulin sensitivity and increased amounts of gut hormone being released in response to an oral glucose dose. 'These mice were probably metabolically more healthy because they were able to respond better to the amount of food arriving in their small intestine,' says Professor de Wet. 'But, still we were unsure of the mechanism; how does ABCC5 manage to get more gut hormone released into the blood stream of these mice?'

Upon further investigation, the team were able to show that ABCC5 is most likely a neuropeptide transporter, meaning its function is to load neuropeptides into vesicles inside cells. The vesicle content is then released by a process called exocytosis, which refers to the series of events triggered when the receptors in enteroendocrine cells detect digested food, culminating in the secretion of hormones from these cells. 'Neuropeptides are information molecules, and these information molecules can be dumped into the circulation to tell your body how to respond to the arrival of digested food in the stomach,' says Professor de Wet. Once the vesicle content is released, the hormones are then free to act on downstream targets.

For the first time, the role of ABCC5 in glucose metabolism and in the regulation of metabolism in humans has been established. The de Wet Group has been able to find a direct link between ABCC5, its metabolic impact as predicted in the Genome-Wide Association Study, and the specific function this ABC transporter has in the gut.

The full publication, 'Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP‐1,' is available to read in the journal Obesity.