Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance

Dongryeol Ryu, Woo Young Seo, Young Sil Yoon, Yo Na Kim, Su Sung Kim, Hye Jin Kim, Tae Sik Park, Cheol Soo Choi, Seung-Hoi Koo

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-Diet-induced obesity (DIO) is linked to peripheral insulin resistance-a major predicament in type 2 diabetes. This study aims to identify the molecular mechanism by which DIOtriggered endoplasmic reticulum (ER) stress promotes hepatic insulin resistance in mouse models. RESEARCH DESIGN AND METHODS-C57BL/6 mice and primary hepatocytes were used to evaluate the role of LIPIN2 in ER stress-induced hepatic insulin resistance. Tunicamycin, thapsigargin, and lipopolysaccharide were used to invoke acute ER stress conditions. To promote chronic ER stress, mice were fed with a high-fat diet for 8-12 weeks. To verify the role of LIPIN2 in hepatic insulin signaling, adenoviruses expressing wild-type or mutant LIPIN2, and shRNA for LIPIN2 were used in animal studies. Plasma glucose, insulin levels as well as hepatic free fatty acids, diacylglycerol (DAG), and triacylglycerol were assessed. Additionally, glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed to evaluate the metabolic phenotype of these mice. RESULTS-LIPIN2 expression was enhanced in mouse livers by acute ER stress-inducers or by high-fat feeding. Transcriptional activation of LIPIN2 by ER stress is mediated by activating transcription factor 4, as demonstrated by LIPIN2 promoter assays, Western blot analyses, and chromatin immunoprecipitation assays. Knockdown of hepatic LIPIN2 in DIO mice reduced fasting hyperglycemia and improved hepatic insulin signaling. Conversely, overexpression of LIPIN2 impaired hepatic insulin signaling in a phosphatidic acid phosphatase activity - dependent manner. CONCLUSIONS-These results demonstrate that ER stress-induced LIPIN2 would contribute to the perturbation of hepatic insulin signaling via a DAG-protein kinase C ε-dependent manner in DIO mice.

Original languageEnglish
Pages (from-to)1072-1081
Number of pages10
JournalDiabetes
Volume60
Issue number4
DOIs
Publication statusPublished - 2011 Apr 1
Externally publishedYes

Fingerprint

Endoplasmic Reticulum Stress
Insulin Resistance
Liver
Insulin
Obesity
Diet
Activating Transcription Factor 4
Phosphatidate Phosphatase
Diacylglycerol Kinase
Glucose
Tunicamycin
Thapsigargin
Chromatin Immunoprecipitation
Diglycerides
High Fat Diet
Pyruvic Acid
Inbred C57BL Mouse
Nonesterified Fatty Acids
Adenoviridae
Hyperglycemia

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ryu, D., Seo, W. Y., Yoon, Y. S., Kim, Y. N., Kim, S. S., Kim, H. J., ... Koo, S-H. (2011). Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. Diabetes, 60(4), 1072-1081. https://doi.org/10.2337/db10-1046

Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. / Ryu, Dongryeol; Seo, Woo Young; Yoon, Young Sil; Kim, Yo Na; Kim, Su Sung; Kim, Hye Jin; Park, Tae Sik; Choi, Cheol Soo; Koo, Seung-Hoi.

In: Diabetes, Vol. 60, No. 4, 01.04.2011, p. 1072-1081.

Research output: Contribution to journalArticle

Ryu, D, Seo, WY, Yoon, YS, Kim, YN, Kim, SS, Kim, HJ, Park, TS, Choi, CS & Koo, S-H 2011, 'Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance', Diabetes, vol. 60, no. 4, pp. 1072-1081. https://doi.org/10.2337/db10-1046
Ryu D, Seo WY, Yoon YS, Kim YN, Kim SS, Kim HJ et al. Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. Diabetes. 2011 Apr 1;60(4):1072-1081. https://doi.org/10.2337/db10-1046
Ryu, Dongryeol ; Seo, Woo Young ; Yoon, Young Sil ; Kim, Yo Na ; Kim, Su Sung ; Kim, Hye Jin ; Park, Tae Sik ; Choi, Cheol Soo ; Koo, Seung-Hoi. / Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. In: Diabetes. 2011 ; Vol. 60, No. 4. pp. 1072-1081.
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AU - Kim, Hye Jin

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AU - Choi, Cheol Soo

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N2 - OBJECTIVE-Diet-induced obesity (DIO) is linked to peripheral insulin resistance-a major predicament in type 2 diabetes. This study aims to identify the molecular mechanism by which DIOtriggered endoplasmic reticulum (ER) stress promotes hepatic insulin resistance in mouse models. RESEARCH DESIGN AND METHODS-C57BL/6 mice and primary hepatocytes were used to evaluate the role of LIPIN2 in ER stress-induced hepatic insulin resistance. Tunicamycin, thapsigargin, and lipopolysaccharide were used to invoke acute ER stress conditions. To promote chronic ER stress, mice were fed with a high-fat diet for 8-12 weeks. To verify the role of LIPIN2 in hepatic insulin signaling, adenoviruses expressing wild-type or mutant LIPIN2, and shRNA for LIPIN2 were used in animal studies. Plasma glucose, insulin levels as well as hepatic free fatty acids, diacylglycerol (DAG), and triacylglycerol were assessed. Additionally, glucose tolerance, insulin tolerance, and pyruvate tolerance tests were performed to evaluate the metabolic phenotype of these mice. RESULTS-LIPIN2 expression was enhanced in mouse livers by acute ER stress-inducers or by high-fat feeding. Transcriptional activation of LIPIN2 by ER stress is mediated by activating transcription factor 4, as demonstrated by LIPIN2 promoter assays, Western blot analyses, and chromatin immunoprecipitation assays. Knockdown of hepatic LIPIN2 in DIO mice reduced fasting hyperglycemia and improved hepatic insulin signaling. Conversely, overexpression of LIPIN2 impaired hepatic insulin signaling in a phosphatidic acid phosphatase activity - dependent manner. CONCLUSIONS-These results demonstrate that ER stress-induced LIPIN2 would contribute to the perturbation of hepatic insulin signaling via a DAG-protein kinase C ε-dependent manner in DIO mice.

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