Cited by 386Liver Disease Diagnosis and TreatmentLipid metabolism and biosynthesisLipid metabolism and disorders

Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance

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Choi, Cheol Soo, Savage, David B., Kulkarni, Ameya, Yu, Xing Xian, Liu, Zhen-Xiang, Morino, Katsutaro, Kim, Sheene, Distefano, Alberto +12 more·2007·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m704213200

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  • Nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.

    “There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
  • Increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of protein kinase C epsilon, resulting in reduced insulin signaling and hepatic insulin resistance.

    “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”

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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.
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
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 › Epidemiology › 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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