3,5-diiodo-l-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet

Mollica, Maria Pina; Lionetti, Lillà; Moreno, María; Lombardi, Assunta; Lange, Pieter de; Antonelli, Alessandro; Lanni, Antonia; Cavaliere, Gina; Barletta, Antonio; Goglia, Fernando

doi:10.1016/j.jhep.2009.03.023

Cited by 106 publications

(100 citation statements)

References 36 publications

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“…In previous studies (Lanni et al 2005, Grasselli et al 2008, T 2 administration was shown to prevent the HFD-induced BW gain and hepatic steatosis, as well as the oxidative stress associated with the fatty liver condition, thus suggesting the therapeutic potential role of T 2 for preventing or treating steatosis (Mollica et al 2009). In this study, the effects of T 2 on the liver of rat fed HFD were examined by assessing the transcription profiles of some important genes involved in lipid metabolism.…”

Section: Discussionmentioning

confidence: 87%

“…This indicates that a stimulation of peroxisomal FFA oxidation occurs upon T 2 administration, in addition to stimulation of the mitochondrial oxidative pathways (Mollica et al 2009, Silvestri et al 2010, in the attempt to reduce the excess fat. Moreover, the increased PPARg levels are in accordance with an action of T 2 in preventing the pro-inflammatory condition associated with the diet.…”

Section: Discussionmentioning

confidence: 96%

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3,5-Diiodo-l-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver

Grasselli¹,

Voci²,

Demori³

et al. 2011

Journal of Endocrinology

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Recent reports demonstrated that 3,5-diiodo-L-thyronine (T 2 ) was able to prevent lipid accumulation in the liver of rats fed a high-fat diet (HFD). In this study, we investigated how the rat liver responds to HFD and T 2 treatment by assessing the transcription profiles of some genes involved in the pathways of lipid metabolism: oxidation, storage and secretion. The mRNA levels of the peroxisome proliferator-activated receptors (PPARa, PPARg and PPARd), and of their target enzymes acyl-CoA oxidase and stearoyl-CoA desaturase were evaluated by real-time RT-PCR. Moreover, the expression of the adipose triglyceride lipase involved in lipid mobilisation, of the main PAT proteins acting in lipid droplet (LD) turnover, and of apoprotein B (apo B), the major protein component of very low-density lipoproteins (VLDLs) were analysed. Overall, our data demonstrated that T 2 administration to HFD rats counteracts most of the hepatic transcriptional changes that occurred in response to the excess exogenous fat. In particular, our results suggest that T 2 may prevent the pathways leading to lipid storage in LDs, promote the processes of lipid mobilisation from LDs and secretion as VLDL, in addition to the stimulation of pathways of lipid oxidation. In conclusion, our findings might give an insight into the mechanisms underlying the anti-steatotic ability of T 2 and help to define the potential therapeutic role of T 2 for preventing or treating liver steatosis.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 96%

3,5-Diiodo-l-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver

Grasselli¹,

Voci²,

Demori³

et al. 2011

Journal of Endocrinology

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“…However, several animal studies in rodents and other species, for example killifish, indicated that 3,5-T2 interferes with the hypothalamus-pituitary-thyroid axis at several levels such as pituitary, thyroid, and peripheral action, thereby displaying a broad spectrum of mechanisms involved such as classical interaction with TR and also rapid effects at the cell membrane and mitochondria (10,12,14,(34)(35)(36)(37)(38)(39)(40) (for a review, see (3)). Action of 3,5-T2 via these different targets and molecular mechanisms might occur at different 3,5-T2 concentrations and depend on acute or chronic exposure (35,37,40), thus possibly explaining the unexpected bell-shaped relationship with serum TSH.…”

Section: Discussionmentioning

confidence: 99%

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

Pietzner

Lehmphul

Friedrich

et al. 2015

Thyroid

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Background: During the last two decades, it has become obvious that 3,5-diiodothyronine (3,5-T2), a wellknown endogenous metabolite of the thyroid hormones thyroxine (T4) or triiodothyronine (T3), not only represents a simple degradation intermediate of the former but also exhibits specific metabolic activities. Administration of 3,5-T2 to hypothyroid rodents rapidly stimulated their basal metabolic rate, prevented highfat diet-induced obesity as well as steatosis, and increased oxidation of long-chain fatty acids. Objective: The aim of the present study was to analyze associations between circulating 3,5-T2 in human serum and different epidemiological parameters, including age, sex, or smoking, as well as measures of anthropometry, glucose, and lipid metabolism. Methods: 3,5-T2 concentrations were measured by a recently developed immunoassay in sera of 761 euthyroid participants of the population-based Study of Health in Pomerania. Subsequently, analysis of variance and multivariate linear regression analysis were performed. Results: Serum 3,5-T2 concentrations exhibited a right-skewed distribution, resulting in a median serum concentration of 0.24 nM (1st quartile: 0.20 nM; 3rd quartile: 0.37 nM). Significant associations between 3,5-T2 and serum fasting glucose, thyrotropin (TSH), as well as leptin concentrations were detected ( p < 0.05). Interestingly, the association to leptin concentrations seemed to be mediated by TSH. Age, sex, smoking, and blood lipid profile parameters did not show significant associations with circulating 3,5-T2. Conclusion: Our findings from a healthy euthyroid population may point toward a physiological link between circulating 3,5-T2 and glucose metabolism.

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“…35 The central role of CPT-1 in the development of hepatic steatosis has also been shown both in vivo and in vitro: moderate overexpression 36 or induction of CPT-1 has been shown to improve diet-induced steatosis of the liver in different NASH models. 37,38 By contrast, a reduction of CPT-1 activity along with other mitochondrial defects, which preceded the development of steatosis and NASH, has been implicated as leading cause for disease development in the Otsuka Long-Evans Tokushima Fatty rat model of NASH. 39 In further support of a contribution of impaired mitochondrial b-oxidation to steatosis, inhibition of CPT-1 has been identified as a possible underlying mechanism in drug-induced steatosis.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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3,5-diiodo-l-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet

Cited by 106 publications

References 36 publications

3,5-Diiodo-l-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver

3,5-Diiodo-l-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

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