Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD

Abstract

Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of -oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16-C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain-to-intermediate-chain acylcarnitine ratio, a marker of efficiency of-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (<0.001). Additionally, multiple linear regression revealed that the long-chain-to-intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16-C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16-C20 FFAs coupled with impaired -oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.

Asymmetrical flow field-flow fractionation for improved characterization of human plasma lipoproteins

“…Specific fragmentation in MS2 allows accurate identification of unique lipids in MS1 as described previously. [32, 41] Figure 4 (ESM Table S1) shows that 277 lipids species in the LDL fraction and 278 species in the HDL fraction are identified in UC-prepared samples in positive MS mode. Similarly, 141 lipids in both LDL and HDL fractions are found in UC-prepared samples in negative mode.…”

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

“…Slight differences in the magnitude of changes are most likely due to the variation in the intensity of the inflammatory or the fibrotic components among models. While no experimental model recapitulates with close fidelity human CKD, the fact that we found significant correlation between advanced kidney disease and two signatures of FAO reduction (acylcarnitines and CPT1A) in two large patient cohorts attests to the clinical relevance of a FAO-related major metabolic disturbance in human CKD 14 .…”

“…To assess the magnitude of CPT1A overexpression on FAO, we analyzed the capacity to oxidize radiolabeled palmitate by the renal tissue. Functionally, the increase in CPT1A protein in the renal epithelium increased the capacity of kidney tissue to oxidize 14 C-palmitate as reflected in the levels of both 14 Cpalmitate-derived 14 CO2 as well as in 14 C-palmitate-derived acid-soluble products (Fig. 1h).…”

“…Control incubations without cells or tissue samples were also run in parallel. 14 Measurements of oxygen consumption rate. Fatty acid oxidation-associated oxygen consumption rate (OCR) (ligated to oxidative phosphorylation) and extracellular acidification rate (ECAR) (associated with lactate production and glycolysis) were studied using the Seahorse Bioscience metabolic analyzer according to the manufacturer's instructions 30 .…”

“…Metabolite measures were normalized using a logarithmic transformation and scaled to multiples of SD using z-score standardization. Three scores were created according to the number of carbons: short (2-7), medium (8)(9)(10)(11)(12)(13)(14) and long (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) acylcarnitine scores. The sum of the log-transformed values of each carnitine was computed to calculate these scores and a zscore standardization was also applied.…”