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

Research Division (J.P., T.B., E.-Y.K., F.D., J.S., A.B.G., M.E.P.), Joslin Diabetes Center, Boston, Massachusetts 02215; Brigham and Women’s Hospital (B.W.K., E.M., A.C.B.), Boston, Massachusetts 02215; Faulkner Hospital/Partners HealthCare (E.M.), Boston, Massachusetts 02130; Beth Israel Deaconess Medical Center (I.N.), Boston, Massachusetts 02215; Children’s Hospital (P.J.P.), Boston, Massachusetts 02215; and Harvard Medical School (J.P., E.-Y.K., B.W.K., E.M., I.N., P.J.P., A.C.B., A.B.G., M.E.P.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Mary Elizabeth Patti, M.D., Joslin Diabetes Center, One Joslin Place, Room 620, Boston, Massachusetts 02215. 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: 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 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, 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 T₃ (100 µg/100 g body weight); furthermore, T₃-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.