The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index.
Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase C epsilon activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase C epsilon activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation.
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“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [25]
In the citing paper
“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [25]
Citations
Cites
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Research works printed but not linked: 5
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Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
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Self-citationMechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
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The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
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Self-citation
Metadata
- Authors
- Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., Zhang, D., Wang, A., Zhang, X.-M., Kahn, M., Cline, G. W., Pandey, S. K., Geisler, J. G., Bhanot, S., Monia, B. P., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 31
- Pages
- 22678-22688
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1976094170
- Cited by
- 383
- References
- 51
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 17 · 2023: 19 · 2022: 15 · 2021: 17 · 2020: 22 · 2019: 26 · 2018: 22 · 2017: 21 · 2016: 16 · 2015: 31 · 2014: 26 · 2013: 15 · 2012: 20
- FWCI
- 17.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Wellcome Trust
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040936, P30DK045735)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- diacylglycerol acyltransferase 2, DGAT1, antisense oligonucleotides, non-alcoholic fatty liver disease, hepatic steatosis, insulin resistance, triglyceride synthesis, diacylglycerol, protein kinase C epsilon, SREBP-1c, lipogenesis, fatty acid oxidation, high-fat diet, type 2 diabetes
- MeSH terms
- Animals, Diet, Fatty Acids, Fatty Liver, Insulin Resistance, Liver, Male, Oxygen, Triglycerides, Oligonucleotides, Antisense, Rats, Sprague-Dawley, Hepatocytes, Diacylglycerol O-Acyltransferase, Rats
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