Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα Deficiency - PubMed (original) (raw)

Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα Deficiency

Michal Pawlak et al. Mol Endocrinol. 2015 Aug.

Abstract

Acute liver failure (ALF) is a severe and rapid liver injury, often occurring without any preexisting liver disease, which may precipitate multiorgan failure and death. ALF is often associated with impaired β-oxidation and increased oxidative stress (OS), characterized by elevated levels of hepatic reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Peroxisome proliferator-activated receptor (PPAR)α has been shown to confer hepatoprotection in acute and chronic liver injury, at least in part, related to its ability to control peroxisomal and mitochondrial β-oxidation. To study the pathophysiological role of PPARα in hepatic response to high OS, we induced a pronounced LPO by treating wild-type and Pparα-deficient mice with high doses of fish oil (FO), containing n-3 polyunsaturated fatty acids. FO feeding of Pparα-deficient mice, in contrast to control sunflower oil, surprisingly induced coma and death due to ALF as indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, ammonia, and a liver-specific increase of ROS and LPO-derived malondialdehyde. Reconstitution of PPARα specifically in the liver using adeno-associated serotype 8 virus-PPARα in Pparα-deficient mice restored β-oxidation and ketogenesis and protected mice from FO-induced lipotoxicity and death. Interestingly, administration of the ketone body β-hydroxybutyrate prevented FO-induced ALF in Pparα-deficient mice, and normalized liver ROS and malondialdehyde levels. Therefore, PPARα protects the liver from FO-induced OS through its regulatory actions on ketone body levels. β-Hydroxybutyrate treatment could thus be an option to prevent LPO-induced liver damage.

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Figures

Figure 1.

Figure 1.. Impairment of FAO pathways potentiates FO-induced OS and LPO in _Ppar_α-deficient mice.

A, Hepatic TG content in wild-type (WT) and _Ppar_α-deficient mice (KO) gavaged with SO or FO. B, Hepatic expression of FAO genes. C, Hepatic ROS levels. D, Hepatic MDA levels. E and F, Hepatic gene expression of Gsta1 and Faldh. Gene expression values are shown relative to WT mice treated with SO (n = 10/group). *, P < .05; **, P < .01; ***, P < .005; by ANOVA followed by Tukey's post hoc test. Data are presented as mean ± SEM.

Figure 2.

Figure 2.. PPARα deficiency provokes ALF in mice gavaged with high-dose FO.

A, Kaplan-Meier curve of wild-type and _Ppar_α-deficient mice treated with SO or FO (n = 15/group). B and C, Plasma levels of ALT and AST of _Ppar_α-deficient mice before gavage with FO and FO-treated mice in coma (after FO) (n = 10/group). D–G, Plasma levels of ammonia (NH3), lactate, glucose, and β-OHB (n = 10/group); *, P < .05; **, P < .01; ***, P < .005; by paired t test. Data are presented as mean ± SEM.

Figure 3.

Figure 3.. Liver-specific PPARα protects from FO-induced ALF and lipoperoxidation by maintaining FAO and ketogenesis pathways.

A, Kaplan-Meier curve of FO-gavaged wild-type mice (_Ppar_α+/+), AAV-LacZ/_Ppar_α−/−, and AAV-PPARα/_Ppar_α−/− mice (n = 15/group). B, Hepatic ROS levels. C, Hepatic MDA levels. D and E, Hepatic expression of Gsta1 and FAO genes. F, Hepatic TG content. G, Hepatic Hmgcs2 expression. H, Plasma β-OHB levels. Gene expression values are shown relative to WT mice treated with FO (n = 5–6/group). *, P < .05; **, P < .01; ***, P < .005; by ANOVA followed by Tukey's post hoc test. Data are presented as mean ± SEM.

Figure 4.

Figure 4.. β-OHB treatment protects from FO-induced ALF by preventing hepatic OS and LPO.

A, Plasma β-OHB levels in wild-type and _Ppar_α-deficient mice fed control chow diet or gavaged with FO and injected with PBS or sodium β-OHB. B and C, Hepatic expression of Hmgcs2 and FAO genes. D, Hepatic TG content. E, Hepatic ROS levels. F, Hepatic MDA levels. G, Hepatic Gsta1 expression. Gene expression values are shown relative to FO-treated _Ppar_α-deficient mice injected with PBS (n = 5–7/group). H, Kaplan-Meier curve of FO-treated _Ppar_α-deficient mice injected with PBS or β-OHB (n = 15/group). *, P < .05; **, P < .01; ***, P < .005; by ANOVA followed by Bonferroni post hoc test. Comparisons between 2 conditions within 1 genotype were performed by unpaired t test. Data are presented as mean ± SEM.

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