ReviewEctopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function
Introduction
There is an epidemic of obesity and the metabolic syndrome (Met-S) across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular diseases. Several hypotheses including excessive visceral fat deposition have been postulated to explain the metabolic abnormalities in obesity and insulin resistance state. The combination of sedentary life style with ready to eat energy rich food in genetically susceptible individuals predisposes persistently over-nourished individuals to gain weight, and when the energy intake exceeds the storage capacity of subcutaneous white adipose tissue (WAT) [1], [2], it induces lipid accumulation in ectopic sites. Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the world with a prevalence of 20–30% in the general population. It is associated with hepatic insulin resistance and is a risk factor for the development of type 2 diabetes [3], [4], [5]. Interestingly, lipid accumulation in ectopic sites is also a characteristic feature of lipodystrophy, a metabolic disorder in which adipose tissue looses its ability to buffer postprandial influx of fatty acids (FA) [6]. Furthermore, lipid accumulation in muscle and liver contributes also to the age-induced insulin resistance and seems related to the associated impaired mitochondrial function [7], [8]. A strong relationship between glucose and lipid metabolism has been recognized for decades. Indeed, the pioneering studies of Randle et al. postulated that FA could impair insulin stimulated glucose oxidation in muscle [9], [10]. They showed that under fasting condition, lipolysis and the resultant increase in circulating non-esterified fatty acids (NEFA) contribute to the increased reliance on fat oxidation to provide energy, and the generation of fat oxidation by-products suppresses glucose oxidation.
The most common cause of progressive kidney disease in the developed world is diabetic nephropathy (DN), microalbuminuria being one of its earliest manifestations. Albuminuria in DN has been considered to be predominantly a consequence of hyperglycemia and glomerular hyperfiltration. However, microalbuminuria also occurs in non-diabetic insulin resistant subjects in whom it is an independent risk factor for cardiovascular disease [11]. This last decade, studies have shown that lipid accumulation in the kidney may also be the cause of Met-S associated renal injury [12], [13].
Emerging evidence suggests that chronic kidney disease might be a state of acquired lipodystrophy leading to ectopic lipid deposition (i.e. lipid deposition in non-adipose tissues). It is known for decades that chronic kidney disease (CKD) induces dyslipidemia with increased plasma triglycerides. While most studies have focused on the impaired clearance of triglyceride rich lipoproteins in the course of CKD [14], recent studies show that adipose tissue flexibility might be altered during CKD resulting in a loss of white adipose tissue (WAT) and the accumulation of lipids in ectopic sites [15], [16]. In fact, increased visceral fat accumulation as assessed by abdominal computed tomography has been shown in non-diabetic hemodialysis patients compared to controls despite lower body mass index (BMI) [17]. There are reasons to believe that this is an important issue to address, because estimation of body fat content with BMI may not adequately reflect the amount of atherogenic visceral and ectopic adipose tissue specifically in the CKD patients [18]. Most importantly, emerging evidence point toward an important role of ectopic fat accumulation in the pathophysiology of insulin resistance and the associated comorbidities [19].
In the present review, we will address the causes and potential impacts of ectopic lipid accumulation in the context of metabolic diseases with emphasis on its potential mechanisms and consequences during the course of CKD.
Section snippets
Energy imbalance
The most common cause in Western society can be attributed to chronic energy imbalance with energy intake exceeding energy expenditure, and increased substrate delivery to peripheral organs. White adipose tissue (WAT) plays a central role in the management of systemic energy stores as well as in many other processes. Healthy humans respond to excess energy intake by storing this surplus of calories as triglycerides in WAT. In obesity state, energy intake exceeds the storage capacity of adipose
Potential mediators of cellular dysfunction related to ectopic fat accumulation
Lipotoxic cellular dysfunctions and injuries occur through several mechanisms, including the generation of reactive oxygen species (ROS), multiple organellar damage, disruption of intracellular signaling pathways, release of proinflammatory and profibrotic factors, and lipid-induced apoptosis. Excess intracellular NEFA and their metabolites (FA-CoA, DAG, and ceramides) promote insulin resistance and exert deleterious effects on various organs [22], [31].
Liver: hepatic steatosis and insulin resistance
Ectopic lipid accumulation in the liver is now widely known as NAFLD [22] and is closely associated with obesity, insulin resistance, and type 2 diabetes mellitus. In the case of hepatic steatosis, hepatic insulin resistance is associated with decreased insulin-stimulated insulin receptor substrate-2 (IRS-2) tyrosine phosphorylation, leading to the inability of insulin to activate hepatic glycogen synthesis and suppress hepatic glucose production. This hepatic insulin resistance is associated
Potential mechanisms: adipose tissue dysfunction
Experimental CKD is associated with reduction of fat depot sizes, and ectopic lipid redistribution [15], [91], [92]. This is also a common phenomenon associated with aging and lipodystrophic syndromes [6], [7] and could be a key factor in the development of metabolic disorders. Since adipocyte size and number are related to insulin sensitivity, glucose and fatty acid uptake and cytokine release, changes in function and cellular composition of WAT might lead to changes in metabolic state and
Conclusion
Ectopic lipid accumulation in visceral tissues including the kidneys is a common finding in models of metabolic diseases but also in kidney diseases. Lipotoxicity has been proven to account for major manifestations of the Met-S in liver, muscle, heart as well as pancreas. Increasing evidence suggests that it may contribute to kidney cell dysfunction and organ injury. Understanding the pathogenesis of lipid mediated renal and vascular injury will provide new targets for therapeutic intervention.
Disclosure statement
None.
Acknowledgments
The authors gratefully acknowledge Dr. Nicolas J PILLON (The Hospital for Sick Children, University of Toronto, Canada) who kindly allows them the free use of his figure of insulin signaling pathways.
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