title: Thyroid hormone-related regulation of gene expression in human fatty liver.
abstract: 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.
authors: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA.
authors: Jussi
authors: J
authors: Pihlajamäki
authors: Tanner
authors: T
authors: Boes
authors: Eun-Young
authors: EY
authors: Kim
authors: Farrell
authors: F
authors: Dearie
authors: Brian W
authors: BW
authors: Kim
authors: Joshua
authors: J
authors: Schroeder
authors: Edward
authors: E
authors: Mun
authors: Imad
authors: I
authors: Nasser
authors: Peter J
authors: PJ
authors: Park
authors: Antonio C
authors: AC
authors: Bianco
authors: Allison B
authors: AB
authors: Goldfine
authors: Mary Elizabeth
authors: ME
authors: Patti
mesh_terms: 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*
chemical_list: 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