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Liver is an important target for thyroid hormone actions. T3 exerts its effects by two mechanisms: (i) Genomic actions consisting of T3 link to nuclear receptors that bind responsive elements in the promoter of target genes, (ii) non-genomic actions including integrin avb3 receptor-mediated MAPK/ERK and PI3K/Akt/mTOR-C1 activation. SREBP-1a, SREBP-1c, and SREBP-2 are transcription factors involved in the regulation of lipogenic genes. We show in Hep G2 cells that T3 determined a dose- and time-dependent increase in the level of the precursor form of SREBP-1 without affecting SREBP-1 mRNA abundance. T3 also induced phosphorylation of ERK1/2, Akt and of mTORC1 target S6K-P70, and the cytosol-to-membrane translocation of PKC-a. Modulation of SREBP-1 protein level by T3 was dependent on MAPK/ERK, PI3K/Akt/mTOR-C1 pathway activation since the MEK inhibitor PD98059 or the PI3K inhibitor LY294002 abolished the stimulatory effect of T3. Conversely, the effect of T3 on SREBP-1 level was enhanced by using rapamycin, mTOR-C1 inhibitor. These data suggest a negative control of mTOR-C1 target S6K-P70 on PI3K/Akt pathway. The effect of T3 on SREBP-1 content increased also by using PKC inhibitors. These inhibitors increased the action of T3 on Akt phosphorylation suggesting that conventional PKCs may work as negative regulators of the T3-dependent SREBP-1 increase. T3 effects were partially abrogated by tetrac, an inhibitor of the T3-avb3 receptor interaction and partially evoked by T3 analog T3-agarose. These findings support a model in which T3 activates intracellular signaling pathways which may be involved in the increment of SREBP-1 level through an IRES-mediated translation mechanism. J. Cell. Physiol. 227: 2388-2397, 2012.

The 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.

The tricarboxylate carrier of the inner membrane of eel liver mitochondria has been solubilized with Triton X-100 and partially purified by chromatography of the mitochondrial extract on dry hydroxyapatite. The purified fraction has been reconstituted into liposomes and functionally analyzed. The reconstituted carrier protein catalyzed a 1,2,3-benzenetricarboxylate-sensitive citrate uptake in liposomes. The substrate specificity and the inhibitor sensitivity of the tricarboxylate carrier are similar to those previously determined for the same protein of mammalian mitochondria.

Dialyzed rat liver cytosol possesses the ability to stimulate the incorporation of [35S]-methionine into mitochondrial proteins. The addition of dialyzed cytosol stimulates sevenfold the rate of protein synthesis by isolated mitochondria after 10 minutes incubation and the extent of this stimulation increases with the time. Various control experiments indicate that the effect is not artifactual nor does it appear to be brought about by GDP or GTP.