Hypothyroidism down-regulates mitochondrial citrate carrier activity and expression in rat liver

Giudetti, Anna Maria; Leo, Monica; Siculella, Luisa; Gnoni, Gabriele V.

doi:10.1016/j.bbalip.2006.03.021

Cited by 28 publications

(24 citation statements)

References 37 publications

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“…Even low-normal free thyroxin levels in patients with euthyroidism have been associated with insulin resistance (22,23). Thyroid disease induces mitochondrial dysfunction (24)(25)(26)(27), and statins reduce levels of coenzyme Q10, a component of the electron transport chain involved in the process of ATP generation (28), also leading to mitochondrial dysfunction as well as causing reduced insulin release and pancreatic b-cell failure and contributing to the development of DM (29)(30)(31)(32). Downregulation of GLUT4 in adipocytes has also been shown to be a result of statin treatment, an effect that has been explained in terms of reduced isoprenoid biosynthesis (33).…”

Section: Discussionmentioning

confidence: 99%

Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study

et al. 2015

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OBJECTIVETo identify risk factors for the development of statin-associated diabetes mellitus (DM). RESEARCH DESIGN AND METHODSThe study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM. In phase two, the most prominent risk factor identified was confirmed in an observational cohort study at Clalit, the largest health care organization in Israel. Time-dependent Poisson regression multivariable models were performed to assess rate ratios (RRs) with 95% CIs for DM occurrence. RESULTSA total of 39,263 statin nonusers were matched by propensity score to 20,334 highly compliant statin initiators in [2004][2005] CONCLUSIONSHypothyroidism is a risk factor for DM. Subclinical hypothyroidism-associated risk for DM is prominent only upon statin use. Identifying and treating hypothyroidism and subclinical hypothyroidism might reduce DM risk. Future clinical studies are needed to confirm the findings.Thyroid disease is common in the general population. Hypothyroidism and subclinical hypothyroidism are more prevalent in patients with type 2 diabetes mellitus (DM), and it is possible that hypothyroidism is a risk factor for the development of DM. Women with subclinical hypothyroidism are more likely to develop gestational diabetes (1). After restoration of thyroid function, reduction of glucose-stimulated insulin secretion has been shown in patients with hypothyroidism as well as in those with subclinical hypothyroidism (2).

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Section: Discussionmentioning

confidence: 99%

Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study

et al. 2015

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“…Even if hypothyroidism altered the membrane lipid composition (i.e., phospholipids and fatty acids), no significant change was observed in the membrane fluidity, thus indicating that other factors must be responsible for the reduced CiC activity in hypothyroid rats (57). Western and Northern blot analyses clearly indicated that both protein level and mRNA accumulation of hepatic CiC noticeably decreased in the hypothyroid state, providing a plausible pretranslational mechanism of regulation for CiC activity (56). Afterward, this assumption was extensively investigated at the molecular level (57).…”

Section: Thyroid Hormonesmentioning

confidence: 95%

“…In this study, it was postulated that the T 3 -induced change in CiC activity could be ascribed either to a general modification of membrane lipid composition, which increases the membrane fluidity and, in turn, the mobility of the carrier, or to a more localized change of lipid domain (cardiolipin content) surrounding CiC in the mitochondrial membrane (55). Subsequent studies revealed the aspects of the molecular mechanisms by which thyroid hormones, in particular their lack, affect CiC activity and expression, in covariance with the de novo fatty acid synthesis (56,57). It has been demonstrated that hypothyroidism severely downregulates CiC activity (250% vs. euthyroid).…”

Section: Thyroid Hormonesmentioning

confidence: 99%

The mitochondrial citrate carrier: Metabolic role and regulation of its activity and expression

et al. 2009

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SummaryThe citrate carrier (CiC), a nuclear-encoded protein located in the mitochondrial inner membrane, is a member of the mitochondrial carrier family. CiC plays an important role in hepatic lipogenesis, which is responsible for the efflux of acetyl-CoA from the mitochondria to the cytosol in the form of citrate, the primer for fatty acid and cholesterol synthesis. In addition, CiC is a key component of the isocitrate-oxoglutarate and the citrate-malate shuttles. CiC has been purified from various species and its reconstituted function characterized as well as its cDNA isolated and sequenced. CiC mRNA and/or CiC protein levels are high in liver, pancreas, and kidney, but are low or absent in brain, heart, skeletal muscle, placenta, and lungs. A reduction of CiC activity was found in diabetic, hypothyroid, starved rats, and in rats fed on a polyunsaturated fatty acid (PUFA)-enriched diet. Molecular analysis suggested that the regulation of CiC activity occurs mainly through transcriptional and post-transcriptional mechanisms. This review begins with an assessment of the current understanding of CiC structural and biochemical characteristics, underlying the structure-function relationship. Emphasis will be placed on the molecular basis of the regulation of CiC activity in coordination with fatty acid synthesis.

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“…Fatty acids were extracted (Muci et al, 1992), and their corresponding methyl esters were prepared by trans-esterification with 17% methanolic boron trifluoride (BF 3 ) at 65°C for 30 min. Fatty acid methyl esters were then analyzed by gas-liquid chromatography (Giudetti et al, 2006). Peak identification was performed by using known standards, and relative quantification was automatically performed by peak integration.…”

Section: Analysis Of Mitochondrial Lipid Compositionmentioning

confidence: 99%

A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

Serviddio

Bellanti

Giudetti

et al. 2009

J Pharmacol Exp Ther

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Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H 2 O 2 production rate were evaluated in isolated liver mitochondria from rats fed a methionine-and cholinedeficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)-and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H 2 O 2 production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE-and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function.

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Hypothyroidism down-regulates mitochondrial citrate carrier activity and expression in rat liver

Cited by 28 publications

References 37 publications

Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study

Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study

The mitochondrial citrate carrier: Metabolic role and regulation of its activity and expression

A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

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