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


METHODS
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.


METHODS
Recruitment was performed in an academic medical center.


METHODS
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.
Pihlajamäki
Jussi
J
Research Division, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA.
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
D000328:Adult; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance; D007453:Iodide Peroxidase / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054411:Receptors, Leptin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014284:Triiodothyronine / Q000494:pharmacology*
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054411:Receptors, Leptin; D014157:Transcription Factors; D014284:Triiodothyronine; D007453:Iodide Peroxidase