Metabolomic analysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet - PubMed (original) (raw)

Metabolomic analysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet

Liliana F Iannucci et al. Sci Rep. 2017.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide, and is often associated with lipotoxic injury, defective mitochondrial function, and insulin resistance. Thyroid hormones (THs) are important regulators of hepatic lipid metabolism. Among the THs, diiodothyronine (T2) and triiodothyronine (T3) have shown promising results in lowering hepatic fat content in various models of NAFLD. In this study, we used a targeted metabolomics approach to investigate the differential effects of T2 and T3 on the early metabolic adaptation in the livers of rats fed high fat diet (HFD), a period when hepatosteatosis is reversible. Our results showed that both T2 and T3 strongly induced autophagy and intra-hepatic acylcarnitine flux but prevented the generation of sphingolipid/ceramides in animals fed HFD. Interestingly, although both T2 and T3 decreased hepatic fat content, only T2 was able to rescue the impairment in AKT and MAPK/ERK pathways caused by HFD. In summary, we have identified and characterized the effects of T2 and T3 on hepatic metabolism during short-term exposure to HFD. These findings illuminate the common and divergent metabolic pathways by T2 and T3 that also may be important in the prevention and treatment of NAFLD.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1

Figure 1

T2 and T3 reduce hepatic lipid accumulation in HFD fed rats associated with increased acylcarnitine flux. (A) Representative graph showing Triglycerides (TGs) content in rats liver treated respectively with NCD, HFD, HFD+T2, HFD+T3 for 1 week. Values are means ± SEM (n = 4). *P < 0.05 in NCD Vs HFD; #P < 0.05 in HFD Vs HFD+T2/HFD+T3. Metabolomics profiles of (B) short chain acylcarnitines (SCAC), (C) medium chain acylcarnitines (MCAC), (D) long chain acylcarnitines (LCAC) and (E) very long chain acylcarnitines (VLCAC) in NCD, HFD, HFD+T2 and HFD+T3 treated rats. Values are means ± SEM (n = 4). *P < 0.05 in NCD Vs HFD; #P < 0.05 in HFD Vs HFD+T2/HFD+T3.

Figure 2

Figure 2

Administration of T2 and T3 increase lipophagy and FAO regulatory proteins in HFD fed rats. Representative cropped Immunoblots and densitometry showing proteins content of lipolytic and autophagic markers (A,B), and β-oxidative markers (C,D). Values are means ± SEM (n = 4). *P < 0.05 in NCD Vs HFD; #P < 0.05 in HFD Vs HFD+T2/HFD+T3.

Figure 3

Figure 3

HFD-induced Sphingolipids accumulation is prevented by T2 and T3 treatment. Quantitative analysis of Ceramide (A), Sphingomylines and (B) Sphinganine after HFD and HFD+T2/HFD+T3 treatment. Values are means ± SEM (n = 4). *P < 0.05 in NCD Vs HFD; #P < 0.05 in HFD Vs HFD+T2/HFD+T3.

Figure 4

Figure 4

T2 but not T3 affects insulin/growth factor signaling in livers of HFD fed rats. Representative cropped Immunoblot and densitometry of ERK and AKT protein levels showing THs influence on the correlated signaling pathway. Values are means ± SEM (n = 4). *P < 0.05 in NCD Vs HFD; #P < 0.05 in HFD Vs HFD+T2/HFD+T3.

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