Introduction
Obesity is a growing concern in all developed and developing countries. Fat accumulation within the body could lead to serious health complications. Obesity is known to induce kidney disorder and obesity-related glomerulopathy. When glomerular sclerotic pathway and tubular damage occur in obese patients, it could cause lipid accumulation. Therefore, lipotoxicity is a consequence of obesity-related glomerulopathy.
What Is Lipotoxicity?
Lipotoxicity is a condition where the accumulation of harmful lipids could cause organ dysfunction, cell injury, or cell death. Toxic lipids include triglycerides, free fatty acids, lysophosphatidylcholine, cholesterol, and ceramides. Few studies have demonstrated that these harmful lipids could harm kidney disease progression in patients with acute kidney injury, diabetic nephropathy, chronic kidney disease, polycystic renal disease, and obesity-related glomerulopathy.
How Do Lipids Accumulate in Kidneys?
An imbalance in lipid acquisition and disposal leads to their accumulation in the body. Three pathways aid the regulation: lipid uptake, lipid synthesis, fatty acid oxidation, and lipid export.
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Lipid Uptake: Fatty acid transport protein and binding protein helps with free fatty acid transport. These proteins are expressed in distal tubule epithelial cells, podocytes, and interstitial macrophages. However, their presence could be more consistent in fat-fed mice. Rats fed a high-fat diet showed increased accumulation of neutral lipids and phospholipids in the kidneys.
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Lipid Synthesis: Lipids are synthesized within the human body through a complex mechanism of acetyl coenzyme conversion. The fatty acids formed are used to produce triglycerides. Sterol regulatory element binding proteins (SREBP) are responsible for cholesterol synthesis. The increased expression could increase lipid accumulation and the risk of chronic renal disease.
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Lipid Oxidation: The kidney has a large energy requirement for metabolic activities. Oxidation of fatty acids could meet the body's energy needs and has an important role in lipid metabolism. Impairment in fatty acid oxidation could lead to lipid accumulation.
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Lipid Export: Fatty acid oxidation is an important mechanism to reduce renal lipid content. Lipid export has a minor role, and lipid export depends on lipoproteins. Some evidence has suggested that impaired lipid export could lead to renal lipid accumulation.
How Does Lipotoxicity Affect Kidneys?
The kidney is a complex structure consisting of several highly specialized cell types. Since a high volume of blood circulates through the kidney, it gets impacted by the amount of circulating fatty acids. Kidneys are adversely affected by lipid accumulation, dyslipidemia (abnormal increase in fat level), and changes to adipokines in the bloodstream that affect peripheral lipid metabolism. The mechanisms through which kidney functioning is affected are:
Adipokines and Pro-inflammatory Factors: During obesity, the adipose tissue faces an increment in endocrine activity. Therefore, the production of adipokines such as leptin, resistin, and adiponectin becomes deregulated. There is increased production of leptin and resistin but decreased adiponectin production. The adipokines induce kidney damage by mediating endothelial dysfunction, stimulating renal sympathetic nervous activity, and causing oxidative stress and inflammation of the kidneys.
During this time, the fat tissue is responsible for secreting pro-inflammatory factors like chemokines, macrophage stimulating factors, and macrophage migration inhibition factors, which cause macrophage accumulation in the kidney. Animal studies have demonstrated that treating macrophage migration stimulation factor antibodies could reduce leukocyte infiltration within the kidney and prevent proteinuria (protein in urine) and renal loss.
Oxidative Stress and Renal Fibrosis: Since a large number of inflammatory factors migrate to the kidneys, there is an increase in oxygen uptake, resulting in the generation of reactive oxygen species (ROS). The ROS is formed to interfere with the ion transport mechanism of the renal tubule by disrupting the renal blood pressure and inducing oxidative injury to proximal tubules. ROS can also stimulate and increase the presentation of fibrotic molecules that could cause renal fibrosis.
Oxidative stress may also induce endoplasmic reticulum stress by promoting unfolding and activating unfolded protein response. Animal studies have shown that dietary saturated free fatty acids can increase endoplasmic reticulum stress within kidneys.
Insulin Resistance: Insulin resistance can cause adverse effects in kidneys and predominantly in podocytes. Podocytes are one of the components in the glomerular filtration barrier that aids in selective filtration of the molecules. Any damage to the podocytes is irreversible, and damage to podocytes allows leakage of macromolecules in the glomerulus. Therefore causing proteinuria. Podocytes are highly sensitive to insulin stimulation and are greatly affected by insulin resistance.
Disruption of Renin-Angiotensin-Aldosterone System (RAAS) Axis: The fat tissues are responsible for secreting all components of the RAAS system. Excessive fat accumulation causes over-activation of the RAAS system, which leads to hyperfiltration. It increases the physical stress and damage to the glomerular filtration barrier, which affects the podocytes. The loss of podocytes is a chain reaction in which the entire glomerular and nephron function becomes lost. There is a reduction in glomerular filtration rate; a rate below 60 percent is considered pathological. If the pathological state is sustained for long, it can cause chronic kidney or end-stage renal disease.
Renal Lipid Metabolism: Lipotoxicity can disrupt lipid metabolism by increasing protein for lipid synthesis within the kidneys. The excess fatty acids not oxidized are converted into lipid droplets by esterification with glycerol. The presence of lipid droplets within podocytes is a common finding in obese patients. The deregulation of lipid metabolism induces a state of energy depletion that leads to renal cell apoptosis and chronic kidney disease.
Peroxisome Proliferator-Activated Receptor Gamma (PPARy): It is a nuclear receptor that has a role in adipogenesis (formation of adipocytes from stem cells), glucose metabolism, triglyceride storage, and energy homeostasis. There are three forms of the receptor. Type 1 is widely distributed sparsely, Type 2 is present in adipose tissue, and Type 3 is found exclusively in white adipocytes. In kidneys, these receptors can be found in collecting ducts, medullary interstitial cells, juxtaglomerular apparatus, and glomeruli.
The PPARy plays an important role in inducing renal lipotoxicity. Mutation of the receptor gene can disrupt lipid and glucose homeostasis. There is a direct link between gene mutation and the development of type 2 diabetes and obesity.
How Is Renal Lipotoxicity Treated?
Thiazolidinediones are PPARy agonists that produce reno-protective effects. The agonists protect mitochondria, reduce proteinuria, and inhibit renal inflammation and oxidative stress. However, agonist use is restricted to individuals with severe side effects such as bone loss, edema, fluid retention, and increased cardiovascular risk.
Conclusion
Abnormal lipid metabolism can have a detrimental effect on the kidney and other vital organs. However, the mechanism of lipid overload that occurs in the kidney is poorly understood. The mechanism of lipid accumulation within the kidney and its possible side effects have been discussed. Much more research is required to understand the link between lipotoxicity and renal disease.
