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This version published online on June 23, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0212
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Submitted on January 28, 2009
Accepted on June 11, 2009

Thyroid Hormone-Related Regulation of Gene Expression in Human Fatty Liver

Jussi Pihlajamäki, Tanner Boes, Eun-Young Kim, Farrell Dearie, Brian W. Kim, Joshua Schroeder, Edward Mun, Imad Nasser, Peter J. Park, Antonio C. Bianco, Allison B. Goldfine, and Mary Elizabeth Patti*

Research Division, Joslin Diabetes Center, Boston, MA 02215, United States; Brigham and Women's Hospital, Boston, MA 02215, United States; Faulkner Hospital/Partners HealthCare, Boston, MA 02130, United States; Beth Israel Deaconess Medical Center, Boston, MA 02215, United States; Children's Hospital, Boston, MA 02215, United States; Harvard Medical School, Boston, MA 02215, United States

* To whom correspondence should be addressed. E-mail: mary.elizabeth.patti{at}joslin.harvard.edu.

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

Objective: To identify novel transcriptional changes in human liver which could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes (T2DM), and nonalcoholic steatohepatitis (NASH).

Design: We evaluated gene expression in surgical liver biopsies from 13 obese (9 with T2DM) and 5 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 (HFD).

Setting: Recruitment was performed in an academic medical center.

Participants: Individuals undergoing elective surgery for obesity or gallstones.

Results: The top-ranking gene set, downregulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by triodothyronine (T3) 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, SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, PCMT1) and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver following injection of C57BL/6J mice with T3 (100 µg/100 g body weight); furthermore, T3-induced increases in expression of these genes were abolished by HFD. 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.
Key words: Fatty liver • thyroid hormones • gene expression






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