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LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney.

Feingold KR, Wang Y, Moser A, Shigenaga JK, Grunfeld C - J. Lipid Res. (2008)

Bottom Line: Here we confirm these findings and define potential mechanisms.Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice.Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8).

View Article: PubMed Central - PubMed

Affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA, USA. kfngld@itsa.ucsf.edu

ABSTRACT
Inflammation produces marked changes in lipid metabolism, including increased serum fatty acids (FAs) and triglycerides (TGs), increased hepatic TG production and VLDL secretion, increased adipose tissue lipolysis, and decreased FA oxidation in liver and heart. Lipopolysaccharide (LPS) also increases TG and cholesteryl ester levels in kidneys. Here we confirm these findings and define potential mechanisms. LPS decreases renal FA oxidation by 40% and the expression of key proteins required for oxidation of FAs, including FA transport protein-2, fatty acyl-CoA synthase, carnitine palmitoyltransferase-1, medium-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase. Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. LPS also caused a reduction in renal mRNA levels of PPARalpha (75% decrease), thyroid hormone receptor alpha (TRalpha) (92% decrease), and TRbeta (84% decrease), whereas PPARbeta/delta and gamma were not altered. Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8). Decreased renal FA oxidation could be a by-product of the systemic coordinated host response to increase FAs and TGs available for host defense and/or tissue repair. However, the kidney requires energy to support its transport functions, and the inability to generate energy via FA oxidation might contribute to the renal failure seen in severe sepsis.

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Effect of LPS on peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR) mRNA levels. A: Effect of 16 h LPS administration in female mice on PPAR mRNA levels utilizing QPCR. First-strand cDNA was synthesized from mouse kidney total RNA, and real-time PCR was carried out as described in Materials and Methods. The Ct values were 24 for PPARα, 24 for PPARβ/δ, and 28 for PPARγ. Data (means ± SE, n = 4) are expressed as a percentage of controls. *** P < 0.001. B, C: Effect of 16 h LPS administration in female mice on levels of TR and malic enzyme (ME). Poly(A)+ RNA was isolated from frozen kidney samples, and Northern blot analysis was performed as described in Materials and Methods. Ten micrograms was loaded per lane. Data (means ± SE, n = 5) are expressed as a percentage of controls. *** P < 0.001.
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fig3: Effect of LPS on peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR) mRNA levels. A: Effect of 16 h LPS administration in female mice on PPAR mRNA levels utilizing QPCR. First-strand cDNA was synthesized from mouse kidney total RNA, and real-time PCR was carried out as described in Materials and Methods. The Ct values were 24 for PPARα, 24 for PPARβ/δ, and 28 for PPARγ. Data (means ± SE, n = 4) are expressed as a percentage of controls. *** P < 0.001. B, C: Effect of 16 h LPS administration in female mice on levels of TR and malic enzyme (ME). Poly(A)+ RNA was isolated from frozen kidney samples, and Northern blot analysis was performed as described in Materials and Methods. Ten micrograms was loaded per lane. Data (means ± SE, n = 5) are expressed as a percentage of controls. *** P < 0.001.

Mentions: PPARα stimulates the expression of the genes in the FA oxidation pathway that were decreased in the kidney after LPS administration (11, 12). Therefore, we next determined the effect of LPS administration on the mRNA levels of the three PPAR isoforms in mouse kidney. As shown in Fig. 3A, PPARα mRNA levels were decreased by 75% in the kidney of LPS-treated animals. In contrast, the mRNA levels of PPARβ/δ and PPARγ were not altered in the kidney of LPS-treated animals. Unfortunately, due to the presence of numerous nonspecific bands, we were unable to measure PPARα protein levels in the kidney by Western blotting using several commercially available antibodies (Cayman Chemical, R and D Systems, and Santa Cruz Biotechnology). These data indicate that LPS treatment specifically decreases the expression of PPARα in the kidney. Previously, we found a 50% decrease in RXRα, which is an obligate partner for PPARα in the kidney (2, 21).


LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney.

Feingold KR, Wang Y, Moser A, Shigenaga JK, Grunfeld C - J. Lipid Res. (2008)

Effect of LPS on peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR) mRNA levels. A: Effect of 16 h LPS administration in female mice on PPAR mRNA levels utilizing QPCR. First-strand cDNA was synthesized from mouse kidney total RNA, and real-time PCR was carried out as described in Materials and Methods. The Ct values were 24 for PPARα, 24 for PPARβ/δ, and 28 for PPARγ. Data (means ± SE, n = 4) are expressed as a percentage of controls. *** P < 0.001. B, C: Effect of 16 h LPS administration in female mice on levels of TR and malic enzyme (ME). Poly(A)+ RNA was isolated from frozen kidney samples, and Northern blot analysis was performed as described in Materials and Methods. Ten micrograms was loaded per lane. Data (means ± SE, n = 5) are expressed as a percentage of controls. *** P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2533407&req=5

fig3: Effect of LPS on peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR) mRNA levels. A: Effect of 16 h LPS administration in female mice on PPAR mRNA levels utilizing QPCR. First-strand cDNA was synthesized from mouse kidney total RNA, and real-time PCR was carried out as described in Materials and Methods. The Ct values were 24 for PPARα, 24 for PPARβ/δ, and 28 for PPARγ. Data (means ± SE, n = 4) are expressed as a percentage of controls. *** P < 0.001. B, C: Effect of 16 h LPS administration in female mice on levels of TR and malic enzyme (ME). Poly(A)+ RNA was isolated from frozen kidney samples, and Northern blot analysis was performed as described in Materials and Methods. Ten micrograms was loaded per lane. Data (means ± SE, n = 5) are expressed as a percentage of controls. *** P < 0.001.
Mentions: PPARα stimulates the expression of the genes in the FA oxidation pathway that were decreased in the kidney after LPS administration (11, 12). Therefore, we next determined the effect of LPS administration on the mRNA levels of the three PPAR isoforms in mouse kidney. As shown in Fig. 3A, PPARα mRNA levels were decreased by 75% in the kidney of LPS-treated animals. In contrast, the mRNA levels of PPARβ/δ and PPARγ were not altered in the kidney of LPS-treated animals. Unfortunately, due to the presence of numerous nonspecific bands, we were unable to measure PPARα protein levels in the kidney by Western blotting using several commercially available antibodies (Cayman Chemical, R and D Systems, and Santa Cruz Biotechnology). These data indicate that LPS treatment specifically decreases the expression of PPARα in the kidney. Previously, we found a 50% decrease in RXRα, which is an obligate partner for PPARα in the kidney (2, 21).

Bottom Line: Here we confirm these findings and define potential mechanisms.Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice.Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8).

View Article: PubMed Central - PubMed

Affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA, USA. kfngld@itsa.ucsf.edu

ABSTRACT
Inflammation produces marked changes in lipid metabolism, including increased serum fatty acids (FAs) and triglycerides (TGs), increased hepatic TG production and VLDL secretion, increased adipose tissue lipolysis, and decreased FA oxidation in liver and heart. Lipopolysaccharide (LPS) also increases TG and cholesteryl ester levels in kidneys. Here we confirm these findings and define potential mechanisms. LPS decreases renal FA oxidation by 40% and the expression of key proteins required for oxidation of FAs, including FA transport protein-2, fatty acyl-CoA synthase, carnitine palmitoyltransferase-1, medium-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase. Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. LPS also caused a reduction in renal mRNA levels of PPARalpha (75% decrease), thyroid hormone receptor alpha (TRalpha) (92% decrease), and TRbeta (84% decrease), whereas PPARbeta/delta and gamma were not altered. Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8). Decreased renal FA oxidation could be a by-product of the systemic coordinated host response to increase FAs and TGs available for host defense and/or tissue repair. However, the kidney requires energy to support its transport functions, and the inability to generate energy via FA oxidation might contribute to the renal failure seen in severe sepsis.

Show MeSH
Related in: MedlinePlus