Thyroid hormone-related regulation of gene expression in human fatty liver.
Open accessAbstract
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.
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A high-fat diet can reduce expression of transcriptional regulators necessary for T3 signaling in the liver.
“For example, there is considerable evidence that a high-fat diet can reduce the expression of transcriptional regulators that are necessary for T3 signaling in the liver (73–75).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [74]
The Results section reports reduced expression of several thyroid-receptor coactivators or corepressors in the livers of obese humans. It also reports that high-fat feeding reduced thyroid-responsive gene expression and blunted the response to T3 in mice, but does not show that the diet reduced expression of those transcriptional regulators. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn obese individuals, surgical liver biopsies identified sets of downregulated genes that were previously demonstrated to be positively regulated by T3.
“Furthermore, the study of surgical liver biopsies of obese individuals identified sets of downregulated genes previously demonstrated to be positively regulated by T3 (74).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [74]
Similar patterns were observed in obese subjects with established type 2 DM.
“Similar patterns were observed in obese subjects with established type 2 DM.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [232]
In the first study, severe obesity (mean BMI 52 kg/m2) was associated with reduced expression of seven of 25 genes encoding OXPHOS genes; expression of these genes was inversely correlated with hepatic lipid accumulation and paralleled by reduced expression of PGC-1α and genes known to be regulated by thyroid hormone.
“In the first (232), severe obesity (mean BMI 52 kg/m 2 ) was associated with reduced ex-pression of seven of 25 genes encoding OXPHOS genes; expression of these genes was inversely correlated with hepatic lipid accumulation and paralleled by reduced expression of PGC-1␣ and genes known to be regulated by thyroid hormone.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [232]
Reduced expression of OXPHOS genes (e.g., COX7C, ATP5C1) was also observed in mice fed a high-fat diet and normalized by acute therapy with thyroid hormone T3, suggesting that functional hepatic thyroid hormone resistance could contribute to reduced expression of mitochondrial oxidative genes in this context.
“Interestingly, reduced expression of OXPHOS genes (e.g., COX7C, ATP5C1) was also observed in mice fed a high-fat diet and normalized by acute therapy with thyroid hormone T 3suggesting that functional hepatic thyroid hormone resistance could contribute to reduced expression of mitochondrial oxidative genes in this context (232).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [232]
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References 40 · Cited by 164
Research works printed but not linked: 1
- [34]34. **Spiegelman B** 2004 Effect of PGC-1α and PGC-1β on gene expression in myocytes and hepatocytes. http://www.diabetesgenome.org/chipperdb/expt.cgi?id=73 [[Google Scholar](https://scholar.google.com/scholar_lookup?Spiegelman%20B%202004%20Effect%20of%20PGC-1%CE%B1%20and%20PGC-1%CE%B2%20on%20gene%20expression%20in%20myocytes%20and%20hepatocytes.%20http://www.diabetesgenome.org/chipperdb/expt.cgi?id=73)]
- Authors
- Pihlajamäki, J., Boes, T., Kim, E.-Y., Dearie, F., Kim, B. W., Schroeder, J., Mun, E., Nasser, I., Park, P. J., Bianco, A. C., Goldfine, A. B., & Patti, M. E.
- Affiliations
- 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
- Joslin Diabetes Center (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Patti, Mary Elizabeth
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-09-01
- Volume
- 94
- Issue
- 9
- Pages
- 3521-3529
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2741713
- OpenAlex
- W2011518200
- Cited by
- 164
- References
- 40
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 10 · 2023: 13 · 2022: 10 · 2021: 12 · 2020: 6 · 2019: 17 · 2018: 8 · 2017: 21 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 8
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-062948, DK70648, R01DK070648, R01DK060837, DK060837, R01DK062948)
- National Center for Research Resources (M01RR001032)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- thyroid hormones, triiodothyronine, hepatic steatosis, hepatic gene expression, obesity, type 2 diabetes, nonalcoholic steatohepatitis, hepatic lipid accumulation, insulin resistance, high-fat diet, energy metabolism genes, liver fat, thyroid hormone resistance
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adult, Animals, Diabetes Mellitus, Type 2, Fatty Liver, Female, Gene Expression Regulation, Heat-Shock Proteins, Humans, Insulin Resistance, Iodide Peroxidase, Liver, Male, Mice, Inbred C57BL, Middle Aged, Transcription Factors, Triiodothyronine, Mice, Receptors, Leptin
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