Researchers at the Francis Crick Institute have found out how microscopic structures called lipid droplets may help to prevent a high-fat diet causing kidney damage.
The work in fruit flies, published in PLoS Biology opens up a new research avenue for developing better treatments for chronic kidney disease.
Eating foods high in fats can cause inflammation and metabolic stress in the kidneys, leading to chronic disease, which in severe cases requires dialysis or a transplant. And with obesity on the rise globally, it’s a growing problem—around 10% of people in the UK are living with chronic kidney disease.
Scientists at the Crick have been studying a common characteristic of the disease, the appearance of lipid droplets inside kidney cells, to solve a long-standing mystery of whether this protects or harms kidney function.
Chewing the fat
Working with electron microscopy experts at the Crick, the team used the sophisticated genetic methods available in the fruit fly (Drosophila) to show that lipid droplets protect the renal system against damage from excess dietary fats.
When fed a high-fat diet, lipid droplets accumulate inside nephrocytes, the flies’ equivalent of human kidney cells called podocytes. Here, the droplets act as a ‘safe haven’ for storing excess fats away from the rest of the cell.
ATGL does this by feeding the fats in a digestible form to nearby mitochondria, where they can be broken down into less toxic molecules.
Lipid droplets are essential for the protective process as when the scientists used genetic methods to prevent their formation, the fats left free inside the nephrocytes caused substantial damage and impaired kidney function.
Alex Gould, head of the Physiology and Metabolism Laboratory at the Crick and lead researcher of the study says: “It has been known for many years that lipid droplets pop up in a wide range of diseases, all the way from diabetes to brain cancer. What’s been far less clear is whether they are making things better or worse.”
“It’s exciting to find that lipid droplets are an essential part of the kidney’s fight back against fat overload. These fascinating structures are turning out to be so much more than tiny balls of fat, and we now want to find out whether their protective role in the kidney also applies to other disease contexts.”
From flies to the clinic
The scientists also found that boosting the expression of the ATGL enzyme in fruit flies was able to repair most of the damage caused by a high-fat diet, restoring normal function to the kidney cells.
Fruit flies are a useful model for understanding the biology of kidney disease in humans because there are important similarities in the renal systems of both species, including the presence of the ATGL enzyme.
Ola Lubojemska, who carried out much of this work in the Physiology and Metabolism Laboratory at the Crick, explains: “These findings are at an early stage but open up a new direction for clinical research into chronic kidney disease. It may, for example, be possible to develop a drug that boosts the ATGL enzyme in renal patients. This would allow excess dietary fats to be more efficiently detoxified by kidney cells, thus improving kidney function.”
Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus (DM) characterized by an increased urinary albumin excretion rate and declined renal function . Approximately 40% of DM patients develop DKD; therefore, DKD is the leading cause of end-stage renal disease (ESRD) and renal failure . According to the International Diabetes Federation (IDF) survey in 2017, there are 451 million (age 18-99 years) people worldwide suffering from diabetes mellitus, and the number is expected to increase to 693 million by 2045 .
The pathogenesis of DKD is relatively complex, and there is growing evidence for genetic factors contributing to DKD susceptibility. Many studies have provided compelling data that DKD has genetic tendency, and familial aggregation additionally indicates that genetic factors play an important role in the etiology of the disease [4, 5]. Genetic research may help to reveal the pathobiology of DKD and uncover potential targets for its treatment.
Recent studies have shown accumulation of fatty acids (FAs) and triglycerides (TGs) in the kidneys of patients with DKD, in a diabetic animal model, and in tubular cells exposed to high-glucose (HG) conditions, which thereby lead to kidney dysfunction [6–8]. Adipose triglyceride lipase (ATGL), encoded by the PNPLA2 gene, is an important component of the lipolytic process and the rate-limiting enzyme for the initiation of TG catabolism [9, 10]. It is reported that ATGL deficiency can impair the renal fatty acid metabolism, which may lead to renal lipid accumulation, proteinuria, and glomerular filtration barrier dysfunction [11, 12]. The relationship between ATGL and kidney injuries in diabetic patients remains unclear.
PNPLA2 is a susceptibility gene of nonalcoholic fatty liver disease (NAFLD) in an obese population . Rs28633403 (A>G) and rs1138714 (A>G) are tagSNPs in PNPLA2 gene with the frequency of minor allele greater than 5%, and rs1138693 (T>C) is a missence polymorphism (L481P) in coding sequence. Genetic studies in obese individuals have shown that rs1138714 was associated with fat mass percentage and volume of subcutaneous adipose tissue, and rs28633403 was related to fat mass percentage and subcutaneous adipose tissue. For SNP rs1138693, it is a risk factor for susceptibility to increased levels of Aminotransferase (AST) enzyme . However, the association of the SNPs with DKD is still unclear. In this study, we selected these 3 SNPs in PNPLA2 gene to explore their association with DKD in type 2 diabetic patients.
To the best of our knowledge, this is the first case-control association study to explore the role of PNPLA2 in the pathogenesis of DKD. In this study, we aimed to evaluate the contribution of PNPLA2 gene polymorphisms to the progression of DKD in patients with type 2 diabetes in a Chinese Han population.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352120/
More information: Aleksandra Lubojemska et al. Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease, PLOS Biology (2021). DOI: 10.1371/journal.pbio.3001230