Am J Physiol Renal Physiol. 2014 Feb 15;306(4):F401-9.

Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2.
 

Kampe K, Sieber J, Orellana JM, Mundel P, Jehle AW.

Dept. of Biomedicine, Molecular Nephrology, Rm. 303, Univ. Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland. andreas.jehle@unibas.ch.

 

ABSTRACT

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR induced FAO measured with tritium labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress and it was markedly reduced in ACC-1/–2 double silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

KEYWORDS: AMPK; apoptosis; diabetic nephropathy; palmitic acid; β-oxidation

PMID: 24338821

 

Supplement:

Diabetic nephropathy (DN) is the major cause of end-stage renal disease, and most affected patients have type 2 diabetes. In DN excessive lipid droplets can be found in different renal cell types including podocytes which form the outer layer of the filtration barrier in the glomerulus. Accumulation of lipids in non-adipose tissues can contribute to cellular dysfunction and cell death, a phenomenon that is called lipotoxicity. Elevated plasma free fatty acids (FFAs) and disturbed FFA metabolism are thought to contribute to lipotoxicity and are emerging as important players in the pathogenesis of DN.

Recently, saturated FFAs such as palmitic acid were found to induce endoplasmic reticulum stress (ER) and podocyte death. In addition, FFA metabolism was reported to be regulated in glomeruli of type 2 diabetic patients with an expression profile suggesting a disposition for increased fatty acid oxidation.

The primary focus of the present study was to elucidate the role of fatty acid oxidation (FAO) in palmitic acid induced podocyte death. As there is evidence from genome wide association studies (GWAS) suggesting that acetyl-CoA carboxylase (ACC) 2, an important enzyme in FAO, is involved in pathogenesis of DN (Fig.1) the role of ACC2 and its isoform ACC1 was investigated by gene silencing in podocytes.

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Figure 1: GWAS identified a SNP in a noncoding region of ACC2 to be associated with proteinuria in type 2 diabetic patients. The SNP results in increased expression of ACC2, which potentially downregulates fatty acid oxidation and leads to accumulation of toxic fatty acids in the kidney and particularly in podocytes.

f2 Figure 2: AICAR and adiponectin upregulate fatty acid oxidation (FAO) via the AMPK-ACC-CPT1 pathway. AICAR and adiponectin activate AMPK and consequently inhibit ACC1 and ACC2 in podocytes resulting in decreased formation of malonyl-CoA and disinhibition of CPT1. Increased activity of CPT 1, the rate limiting enzyme of FAO, is finally leading to stimulation of β-oxidation.

 

Functionally, ACCs catalyze the formation of malonly-CoA, which is a potent inhibitor of carnitine palmityltransferase (CPT) 1, the rate limiting enzyme of FAO (Fig. 2).

The present study uncovered that regulation of FAO critically determines the susceptibility of podocytes exposed to palmitic acid. Stimulation of FAO by aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protected podocytes from palmitic acid induced cell death. Conversely inhibition of FAO by etomoxir, a CPT1 inhibitor, aggravated palmitic acid induced cell death and reversed the protective effect of AICAR. The important functional relevance of both ACC1 and ACC2, which catalyze the production of malonyl-CoA, a CPT1 inhibitor, was underlined as only double knock down of ACC1 and ACC2 protected podocytes from palmitic acid induced cell death.

In conclusion, the present study uncovered that regulation of FAO by modulation of the AMPK-ACC-CPT1 pathway critically determines the susceptibility of podocytes exposed to palmitic acid. Our findings are of clinical interest and they relevantly amend recent clinical and experimental studies indicating a potentially important role of FFA metabolism and particularly FAO in the pathogenesis of DN.

 

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