Dataset Information

Thyroid hormone-related regulation of gene expression in human fatty liver.

ABSTRACT:

Context

Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified.

Objective

The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis.

Design

We evaluated gene expression in surgical liver biopsies from 13 obese (nine with type 2 diabetes) and five control subjects using Affymetrix U133A microarrays. PCR validation was performed in liver biopsies using an additional 16 subjects. We also tested thyroid hormone responses in mice fed chow or high-fat diet.

Setting

Recruitment was performed in an academic medical center.

Participants

Individuals undergoing elective surgery for obesity or gallstones participated in the study.

Results

The top-ranking gene set, down-regulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by T(3) in human skeletal muscle (n = 399; P < 0.001; false discovery rate = 0.07). This gene set included genes related to RNA metabolism (SNRPE, HNRPH3, TIA1, and SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, and PCMT1), and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver after injection of C57BL/6J mice with T(3) (100 microg/100 g body weight); furthermore, T(3)-induced increases in expression of these genes were abolished by high-fat diet. In agreement, expression of these genes inversely correlated with liver fat content in humans.

Conclusions

These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver.

SUBMITTER: Pihlajamaki J

PROVIDER: S-EPMC2741713 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Publications

Thyroid hormone-related regulation of gene expression in human fatty liver.

Pihlajamäki Jussi J Boes Tanner T Kim Eun-Young EY Dearie Farrell F Kim Brian W BW Schroeder Joshua J Mun Edward E Nasser Imad I Park Peter J PJ Bianco Antonio C AC Goldfine Allison B AB Patti Mary Elizabeth ME

The Journal of clinical endocrinology and metabolism 20090623 9

<h4>Context</h4>Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified.<h4>Objective</h4>The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis.<h4>Design</h4>We evaluated gene expression in surgical liver biopsies from 13 obese (nine with ...[more]

PMID: 19549744

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Project description:We reported previously that the expression of the gene encoding MUC5AC mucin in human airway epithelial cells is controlled by retinoic acid via the retinoic acid receptor (RAR)-alpha and that 3,3',5-tri-iodothyronine (T(3)) inhibits the expression of MUC5AC. The purpose of the present study was to identify mechanisms mediating the effect of T(3). T(3) has been shown to inhibit gene expression via several mechanisms, either by enhancing or repressing the transcription of target genes or by the regulation of post-transcriptional events. Results showed that T(3) strongly inhibited MUC5AC-driven luciferase activity in normal human tracheobronchial epithelial cells that had been transiently transfected with a MUC5AC-luciferase reporter construct; however, it did not affect MUC5AC mRNA stability. These results indicate that T(3) suppresses MUC5AC expression at the transcriptional level. An analysis of deletion constructs showed that deletion of the region downstream of 3 kb resulted in markedly decreased levels of MUC5AC transcription in the absence of T(3) (i.e. under control conditions) as well as a loss of responsiveness to the inhibitory effects of T(3). This suggests that this region might contain elements important for the activation as well as the repression of MUC5AC transcription. To determine whether T(3) modulates retinoic-acid-dependent MUC5AC transcription via an alteration in the abundance of retinoid receptor proteins, we examined the type and abundance of these receptors in nuclear extracts of airway epithelial cells grown in the presence or absence of T(3). Western blots showed that T(3) markedly decreased several types of retinoid receptor while not affecting T(3) receptor proteins. Consistent with this finding were gel-shift assays revealing a decrease in RAR-retinoic acid response element complexes obtained from T(3)-treated cells. We propose that T(3) might inhibit retinoid-dependent MUC5AC expression by decreasing retinoid receptor levels and thereby decreasing the transcriptional activation of this gene for mucins.

Dataset Information

Thyroid hormone-related regulation of gene expression in human fatty liver.

Context

Objective

Design

Setting

Participants

Results

Conclusions

Publications

Thyroid hormone-related regulation of gene expression in human fatty liver.

Similar Datasets

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