Lipotoxicity in Kidney, Heart, and Skeletal Muscle Dysfunction

Abstract

Dyslipidemia is a common nutritional and metabolic disorder in patients with chronic kidney disease. Accumulating evidence supports the hypothesis that prolonged metabolic imbalance of lipids leads to ectopic fat distribution in the peripheral organs (lipotoxicity), including the kidney, heart, and skeletal muscle, which accelerates peripheral inflammation and afflictions. Thus, lipotoxicity may partly explain progression of renal dysfunction and even extrarenal complications, including renal anemia, heart failure, and sarcopenia. Additionally, endoplasmic reticulum stress activated by the unfolded protein response pathway plays a pivotal role in lipotoxicity by modulating the expression of key enzymes in lipid synthesis and oxidation. Here, we review the molecular mechanisms underlying lipid deposition and resultant tissue damage in the kidney, heart, and skeletal muscle, with the goal of illuminating the nutritional aspects of these pathologies.

Keywords: kidney; lipotoxicity; sarcopenia; skeletal muscle; uremia.

Figure 1

Mitochondrial handling of fatty acids and subsequent energy generation. Long-chain fatty acyl-CoA is esterified with carnitine in the cytoplasm and then the carnitine shuttle serves to carry it from the cytosol to the mitochondria, while medium- and short-chain fatty acyl-CoA freely diffuses into the mitochondria. Once the fatty acid is located inside the mitochondrial matrix, two carbons are cleaved from the molecule every cycle to form fatty acetyl-CoA, the process of which is named fatty acid oxidation (β oxidation). The process continues until all of the carbons in the fatty acid are turned into acetyl CoA, which enters the TCA cycle to generate ATP. Oxidation also generates NADH and FADH₂, electrons derived from which are utilized by the five OXPHOS complexes to generate ATP. CPT: Carnitine palmitoyltransferase; CACT: Carnitine-acylcarnitine translocase; CoA: Coenzyme A; LCFA: Long-chain fatty acid; MCFA: Medium-chain fatty acid; SCFA: Short-chain fatty acid; FAO: Fatty acid oxidation; TCA: Tricarboxylic acid; NAD: Nicotinamide adenine dinucleotide; FAD: Flavin adenine dinucleotide; OXPHOS: Oxidative phosphorylation.

Figure 2

Integrated organ pathology caused by lipotoxicity in uremia. In the presence of prolonged nutrient excess or disturbed metabolism, lipids accumulate ectopically in tissues and organs including the kidney, heart, and skeletal muscle. The endpoints of lipotoxicity vary among those targets and include urinary albumin excretion and impaired erythropoietin production in the kidney, heart failure, and insulin resistance and mass reduction (sarcopenia) in the skeletal muscle. EPO: erythropoietin; ER: endoplasmic reticulum; ROS: reactive oxygen species; FA: fatty acid; TNF: tumor necrosis factor; IMCL: intramyocellular lipid; TAG: triacylglycerol.