☆ 4.6 Article

The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance

LABORATORY INVESTIGATION (2015)

期刊

LABORATORY INVESTIGATION

卷 95, 期 12, 页码 1409-1417

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NATURE PUBLISHING GROUP

DOI: 10.1038/labinvest.2015.115

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Medicine, Research & Experimental Pathology

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Institut de Salud Carlos III, Spain [PI12/00338]
FEDER funds

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摘要

The dyslipidemia associated with type 2 diabetes mellitus (T2DM) is an important risk factor for atherosclerotic cardiovascular disease. However, until now little attention has been paid to the role that the intestine might have. The aim of this research was to determine the relation between insulin resistance and intestinal de novo lipogenesis/lipoprotein synthesis in morbidly obese subjects and to study the effect of insulin on these processes. Jejunal mRNA expression of the different genes involved in the intestinal de novo lipogenesis/lipoprotein synthesis was analyzed in three groups of morbidly obese subjects: Group 1 with low insulin resistance (MO-low-IR), group 2 with high insulin resistance (MO-high-IR), and group 3 with T2DM and treatment with metformin (MO-metf-T2DM). In addition, intestinal epithelial cells (IECs) from MO-low-IR were incubated with different doses of insulin/glucose. In Group 2 (MO-high-IR), the jejunal mRNA expression levels of apo A-IV, ATP-citrate lyase (ACLY), pyruvate dehydrogenase (lipoamide) beta (PDHB), and sterol regulatory element-binding protein-1c (SREBP-1c) were significantly higher and acetyl-CoA carboxylase alpha (ACC1) and fatty-acid synthase lower than in Group 1 (MO-low-IR). In Group 3 (MO-nnetf-T2DM), only the ACLY and PDHB mRNA expressions were significantly higher than in Group 1 (MO-low-IR). The mRNA expression of most of the genes studied was significantly linked to insulin and glucose levels. The incubation of IEC with different doses of insulin and glucose produced a higher expression of diacylglycerol acyltransferase 2, microsomal triglyceride transfer protein, apo A-IV, SREBP-1c, and ACC1 when both, glucose and insulin, were at a high concentration. However, with only high insulin levels, there were higher apo A-IV, PDHB and SREBP-1c expressions, and a lower ACLY expression. In conclusion, the jejunum of MO-high-IR has a decreased mRNA expression of genes involved in de novo fatty-acid synthesis and an increase of genes involved in acetyl-CoA and lipoprotein synthesis. This effect is attenuated by metformin. In addition, the expression of most of the genes studied was found to be regulated by insulin.

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DNA methylation profile of genes involved in inflammation and autoimmunity correlates with vascular function in morbidly obese adults

Mohamed M. Ali, Dina Naquiallah, Maryam Qureshi, Mohammed Imaduddin Mirza, Chandra Hassan, Mario Masrur, Francesco M. Bianco, Patrice Frederick, Giulianotti P. Cristoforo, Antonio Gangemi, Shane A. Phillips, Abeer Mahmoud

Summary: In individuals with obesity, there was a higher fraction of methylated genes in the control group compared to obese subjects, while proinflammatory genes showed significantly lower methylation levels in obese individuals. Fifteen genes had significantly higher mRNA levels in obese subjects compared to controls, including CXCL6, TLR5, IL6ST, EGR1, IL15RA, and HDAC4. Methylation percentage was inversely correlated with various cardiometabolic risk factors and positively correlated with parameters associated with vascular function such as FID, NO production, and FMD. This suggests that vascular dysfunction in obese adults may be due to systemic hypomethylation and overexpression of immune-related genes.

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