DGAT1 Is Not Essential for Intestinal Triacylglycerol Absorption or Chylomicron Synthesis

Buhman, Kimberly K.; Smith, Steven J.; Stone, Scot J.; Repa, Joyce J.; Wong, Jinny S.; Knapp, F. F.; Burri, Betty J.; Hamilton, Robert L.; Abumrad, Nada A.; Farese, Robert V.

doi:10.1074/jbc.m202013200

Cited by 221 publications

(201 citation statements)

References 21 publications

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“…In contrast to its high protein expression in small intestine, mMGAT2 protein was not detected in the lower intestinal tract, including cecum, colon, and rectum. The distribution of MGAT is also consistent with that of DGAT1 and DGAT2 mRNA (30), supporting the notion that re-synthesis of triacylglycerol is an obligatory process during dietary fat absorption.…”

Section: Discussionsupporting

confidence: 68%

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

Cao

Hawkins

Brozinick

et al. 2004

Journal of Biological Chemistry

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Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) catalyzes the synthesis of diacylglycerol and differs from the MGAT1 and MGAT3 in tissue distribution at the mRNA level. In addition to the small intestine, MGAT2 mRNA is also expressed at high levels in human liver, the lower gastrointestinal tract, and the mouse kidney, but the physiological significance of such expression has not yet been studied. Using an affinitypurified antibody, the present study investigated the expression of murine MGAT2 protein along the intestinal tract, determined its subcellular localization, and studied its regulation by diet and in db/db mouse. Results demonstrate a high level of MGAT2 expression in the small intestine in a proximal-to-distal gradient that correlated well with both MGAT enzyme activity and fat absorption pattern. In contrast, MGAT2 protein was not detectable in other sections of the digestive tract, including stomach, cecum, colon, and rectum, or other mouse tissues such as kidney, liver, and adipocytes. Immunohistological studies provided direct evidence that the enzyme is expressed not only in the villi, but also in the crypt regions of the small intestine, which suggests that MGAT2 expression occurs prior to the maturation of enterocytes. MGAT2 is localized in the endoplasmic reticulum (ER) in both MGAT2-transfected COS-7 and Caco-2 cells, indicating that the ER is the primary site for dietary fat re-synthesis. MGAT2 expression appeared not to be affected by diabetes in the db/db mouse, however, the total intestinal MGAT activity was significantly enhanced. Finally, an up-regulation of both MGAT2 protein expression and MGAT activity was observed in mice fed a high fat diet, implicating a role of MGAT2 in diet-induced obesity. Taken together, our data suggest a predominant role of MGAT2 in dietary fat absorption.In mammals, the small intestine plays a predominant role in the absorption of dietary lipids (mainly triacylglycerol). The absorption of triacylglycerols by the intestinal tract is a complex process that requires several steps, including the hydrolysis of triacylglycerols by pancreatic lipase in the intestinal lumen, the uptake of released 2-monoacylglycerol and fatty acids into enterocytes, and the reconstitution of triacylglycerol in the enterocytes by the monoacylglycerol pathway where 2-monoacylglycerol and fatty acids are utilized to sequentially re-synthesize diacylglycerol and triacylglycerol by acyl-CoA: monoacylglycerol acyltransferase (MGAT) 1 and acyl-CoA:diacylglycerol acyltransferase (DGAT), respectively. Another pathway involved in the triacylglycerol synthesis is the glycerol 3-phosphate pathway, a de novo pathway that is present in most tissues, including small intestine. The pathway begins with acylation of glycerol 3-phosphate with fatty acyl-CoA producing lysophosphatidic acid, followed sequentially by further acylation and dephosphorylation to yield diacylglycerol (1). Both pathways share the final step converting diacylglycerol to triacylglycerol by DGAT. In the small intestinal muc...

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Section: Discussionsupporting

confidence: 68%

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

Cao

Hawkins

Brozinick

et al. 2004

Journal of Biological Chemistry

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“…Two enzymes that catalyze the final step of triglyceride synthesis, have been identified and named DGAT1 and DGAT2 (5,24). Surprisingly, expression of DGAT1 was found to be significantly reduced (0.62-fold) in Irs2 Ϫ/Ϫ mouse adipose tissue, whereas expression of DGAT2 was clearly increased (3.3-fold, Fig.…”

Section: Decreased Dgat1 and Increased Dgat2 Expression In The Wat Ofmentioning

confidence: 99%

Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Suzuki

Tobe

Aoyama

et al. 2005

Journal of Biological Chemistry

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Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2 ؊/؊ mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2 ؊/؊ mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.We have hypothesized that the size of adipocytes is inversely correlated with insulin sensitivity; namely, that larger adipocytes are associated with insulin resistance and smaller adipocytes are associated with insulin sensitivity (1). Acyl-CoA:diacylglycerol acyltransferase (DGAT) 1 is a key enzyme that catalyzes the final step in mammalian triglyceride synthesis (2), and two DGAT enzymes have been identified (3-5). Although the genes encoding DGAT1 and DGAT2 belong to different gene families, both genes are ubiquitously expressed and the enzymes they encode have similar substrate specificity (5). Dgat1 Ϫ/Ϫ mice have been reported to exhibit normal growth on a chow diet, and to be resistant to diet-induced obesity (6). Interestingly, Dgat1Ϫ/Ϫ mice exhibit increased insulin sensitivity and a leptin-sensitive phenotype associated with decreased tissue triglyceride content, suggesting that DGAT1 is somehow involved in insulin and leptin action throughout the body (7, 8). Recently, Dgat2Ϫ/Ϫ mice have been reported to exhibit marked reduction of triglyceride and fatty acids in the body, suggesting a critical role of DGAT2 in lipogenesis; however, the physiological roles of DGAT2 in adult mice are still unknown because Dgat2 Ϫ/Ϫ mice die soon after birth (9). The insulin receptor substrate (IRS) proteins play a key role in signal transduction from the insulin receptor (10, 11) and are major intracellular phosphorylation targets of activated insulin receptor tyrosine kinase. Irs2 Ϫ/Ϫ mice develop diabetes because of inadequate ␤-cell proliferation combined with insulin resistance (12-14). Another n...

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“…Although targeted deletion of murine DGAT1 has indicated a role for the enzyme in obesity and insulin sensitivity (34,35), the activity of this enzyme is not required for chylomicron formation (36). Similarly, obviation of the major alternate pathway of TG synthesis encoded by the DGAT2 gene significantly reduced but did not eliminate lipoprotein secretion by the liver or intestine (37).…”

mentioning

confidence: 99%

Overexpression of Human Diacylglycerol Acyltransferase 1, Acyl-CoA:Cholesterol Acyltransferase 1, or Acyl-CoA:Cholesterol Acyltransferase 2 Stimulates Secretion of Apolipoprotein B-containing Lipoproteins in McA-RH7777 Cells

Liang¹,

Oelkers

Cui-ying³

et al. 2004

Journal of Biological Chemistry

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DGAT1 Is Not Essential for Intestinal Triacylglycerol Absorption or Chylomicron Synthesis

Cited by 221 publications

References 21 publications

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Overexpression of Human Diacylglycerol Acyltransferase 1, Acyl-CoA:Cholesterol Acyltransferase 1, or Acyl-CoA:Cholesterol Acyltransferase 2 Stimulates Secretion of Apolipoprotein B-containing Lipoproteins in McA-RH7777 Cells

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