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How and Why Do Lipid Droplets Accumulate in Gastric Epithelial Neoplasms?

Munechika Enjoji1*, Motoyuki Kohjima2, Kenji Ohe1 and Kenshi Yao3
1Department of Clinical Pharmacology, Fukuoka University, Japan
2Departments of Hepatology and Pancreatology, Kyushu University Hospital, Japan
3Department of Endoscopy, Fukuoka University Chikushi Hospital, Japan


*Corresponding author: Munechika Enjoji, Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan


Published: 23 Jan, 2017
Cite this article as: Enjoji M, Kohjima M, Ohe K, Yao K. How and Why Do Lipid Droplets Accumulate in Gastric Epithelial Neoplasms?. Ann Pharmacol Pharm. 2017; 2(2): 1016.

Abstract

Under the endoscopic observation with magnification endoscopy and narrow-band imaging, one of the novel findings in gastric neoplasms is white opaque substance (WOS), which is a manifestation of intracellular accumulation of lipid droplets. To elucidate the significance of this WOS formation, detailed lipid metabolism should be understood in gastric membranes. Recently, expression profiles of lipid-metabolism-associated genes in gastric tumor and non-tumor mucosa were investigated and reported. In this article, we explain the lipid accumulation and disturbance of lipid metabolism in gastric neoplasms.


Introduction

Recently, under practical endoscopic use of magnification endoscopy and narrow-band imaging, several novel findings have been reported especially in gastric epithelial neoplasms. For example, the patterns of micro vascular architecture and micro surface structure of the gastric mucosa provided reliable markers for differentiating between benign and malignant neoplasms [1-6]. Moreover, a white opaque substance (WOS) was found within the gastric neoplastic epithelium (adenoma and carcinoma) using magnification endoscopy with narrow-band imaging and the WOS was histologically verified as intracellular accumulation of lipid droplets [7]. We consider that the morphologic analysis of WOS may represent a useful new optical marker for discriminating between benign and malignant neoplasms [8-10]. Generally, development of lipid accumulation may be the result from disturbance of lipid metabolism. However, the precise process of the absorption, accumulation, excretion, and/or consumption of lipids has been unclear both in the normal and neoplastic gastric mucosa. Therefore, our group has analyzed and reported the expression profiles of lipid-metabolism-associated genes in paired gastric tumor and non-tumor mucosa to elucidate the mechanism of WOS/lipid droplet accumulation in gastric neoplasms [11].


Expression Analysis of Lipid-Metabolism-Associated Genes

Our group analyzed lipid-metabolism-associated genes, which have already been well characterized in enterocytes, because gastric intestinal metaplasia is considered to have high risk to develop into gastric adenoma and carcinoma [12-15]. Paired biopsy samples, which were supplied for assessing expression levels of lipid-metabolism-associated genes, were obtained endoscopic ally from neoplastic and adjacent non-tumor areas from 34 patients with gastric epithelial neoplasms (0‒I, 0‒IIa, 0‒IIb, or 0‒IIc according to the Paris endoscopic classification). The background characteristics of the participants are shown in Table 1 [11]. Expression levels were analyzed by real-time reverse-transcription polymerase chain reaction. Expression profiles in gastric adenomas and carcinomas were compared with those in adjacent background mucosa. Gene expression profiles in gastric neoplasms are summarized in (Figure 1). Characteristic expression patterns were as follows 1) Expression levels of genes associated with fatty acid synthesis, sterol regulatory element-binding protein 1c (SREBP-1c), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), were up-regulated in gastric neoplasms, though the difference was only significant for SREBP-1c and DGAT2. 2) Those of genes associated with lipid droplet degradation, adipose triglyceride lipase (ATGL) and comparative gene identification-58 (CGI-58), were down-regulated with significant differences. 3) Those of genes associated with chylomicron assembly, acyl-CoA: cholesterol acyltransferase 2 (ACAT2), microsomal triglyceride transfer protein (MTP), apoB, acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1), and intestinal fatty acid-binding protein (I-FABP), were significantly decreased. 4) Those of genes associated with mitochondrial β-oxidation, peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (CPT1a), and hydroxyacyl-CoA dehydrogenase (HADH), were also significantly decreased.


Figure 1

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Figure 1
Necrotizing fasciitis of left lower limb.

Table 1

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Table 1
Patient’s response to ECT measured periodically.

Lipid Accumulation and WOS in Gastric Tumors

Lipid metabolism in gastric mucosa has not been investigated well and still unclear. Functions of estimated genes in Figure. 1 are conformed to those in enterocytes. Perhaps, gastric mucosa acquire fatty acid from diet-derived triglycerides and de novo lipogenesis. These obtained fatty acids may either be used for consumption or storage, and an imbalance between storage factors (fatty acid uptake, de novo lipogenesis, and lipid droplet biogenesis) and consumption factors (mitochondrial β-oxidation, chylomicron assembly, and lipid droplet degradation) may result in triglycerides/lipid droplets accumulation in the cytoplasm. As shown in Figure. 1, compared with non-tumor mucosa, lipid consumption was attenuated and conversely, lipid storage was promoted in gastric neoplasms, consequently reading to accumulation of lipid droplets and WOS formation. In our endoscopic estimation, WOS was evident in 74.2% of tumor tissues and in 12.9% of non-tumor tissues. It remains unclear whether WOS is associated with carcinogenesis and/or development of gastric tumors. However, we consider that WOS may be a result of the development of gastric cancer, but not a cause. Occasional positivity in gastric intestinal metaplasia [16,17] may indicate the process of carcinogenesis through adenoma to adenocarcinoma. However, further investigations are needed to clarify the association between WOS and carcinogenesis.


Conclusion

Many lipid-metabolism-associated genes in enterocytes are also active in gastric cells. Lipid accumulation and WOS formation in gastric neoplasms is largely caused by a deterioration of lipid consumption (β-oxidation/excretion/lipolysis) and an acceleration of lipogenesis. Further investigation of lipid metabolism in gastric tumors may lead to significance of WOS to be a useful new optical marker for the detection/diagnosis of early gastric cancer.


References

  1. Yao K, Oishi T, Matsui T, Iwashita A. Novel magnified endoscopic findings of microvascular architecture in intramucosal gastric cancer. Gastrointest Endosc. 2002; 56: 279-284.
  2. Yao K, Iwashita A, Kikuchi Y, Yao T, Matsui T, Tanabe H, et al. Novel zoom endoscopy technique for visualizing the microvascular architecture in gastric mucosa. Clin Gastroenterol Hepatol. 2005; 3: S23‒26.
  3. Yao K, Iwashita A, Tanabe H. Novel zoom endoscopy technique for diagnosis of small flat gastric cancer: a prospective, blind study. Clin Gastroenterol Hepatol. 2007; 5: 869‒878.
  4. Ezoe Y, Muto M, Uedo N, Doyama H, Yao K, Oda I, et al. Magnifying narrowband imaging is more accurate than conventional white-light imaging in diagnosis of gastric mucosal cancer. Gastroenterology. 2011; 141: 2017‒2025.
  5. Kanesaka T, Sekikawa A, Tsumura T, Maruo T, Osaki Y, Wakasa T, et al. Dense-type crypt opening seen on magnifying endoscopy with narrow-band imaging is a feature of gastric adenoma. Dig Endosc. 2014; 26: 57‒62.
  6. Yao K, Doyama H, Gotoda T, Ishikawa H, Nagahama T, Yokoi C, et al. Diagnostic performance and limitations of magnifying narrow-band imaging in screening endoscopy of early gastric cancer: A prospective multicenter feasibility study. Gastric Cancer. 2014; 17: 669‒679.
  7. Yao K, Iwashita A, Tanabe H. White opaque substance within superficial elevated gastric epithelial neoplasia as visualized by magnifying endoscopy with narrow-band imaging: a new optical sign for differentiating between adenoma and carcinoma. Gastrointest Endosc. 2008: 68: 574‒580.
  8. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc. 2003; 58: S3‒43.
  9. Yao K, Iwashita A, Nambu M. Nature of white opaque substance in gastric epithelial neoplasms as visualized by magnifying endoscopy with narrow-band imaging. Dig Endosc. 2012: 24: 419‒425.
  10. Ueo T, Yonemasu H, Yada N, Yano S, Ishida T, Urabe M, et al. White opaque substance represents an intracytoplasmic accumulation of lipid droplets: immunohistochemical and immunoelectron microscopic investigation of 26 cases. Dig Endosc. 2013; 25: 147‒155.
  11. Enjoji M, Kohjima M, Ohtsu K, Matsunaga K, Murata Y, Nakamuta M, et al. Intracellular mechanisms underlying lipid accumulation (white opaque substance) in gastric epithelial neoplasms: A pilot study of expression profiles of lipid-metabolism-associated genes. J Gastroenterol Hepatol. 2016; 31: 776‒781.
  12. Uedo N, Ishihara R, Iishi H, Yamamoto S, Yamamoto S, Yamada T, et al. A new method of diagnosing gastric intestinal metaplasia: Narrow-band imaging with magnifying endoscopy. Endoscopy. 2006; 38: 819‒824.
  13. Tahara T, Shibata T, Nakamura M, Yoshioka D, Arisawa T, Hirata I, et al. Light blue crest sign, a favorable marker for predicting the severity of gastric atrophy in the entire stomach. Endoscopy. 2008; 40: 880.
  14. Oya M, Yao T, Nakamura T, Nakanishi K, Tsuneyoshi M. Intestinal phenotypic expression of gastric depressed adenomas and the surrounding mucosa. Gastric Cancer. 2003; 6: 179‒184.
  15. Abraham SC, Montgomery EA, Singh VK. Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology. Am J Surg Pathol. 2002; 26: 1276‒1285.
  16. Matsushita M, Mori S, Uchida K. “White opaque substance” and “light blue crest” within gastric flat tumors or intestinal metaplasia: same or different signs? Gastrointest Endosc. 2009; 70: 402.
  17. Yao K, Nagahama T, Iwashita A. Response. Gastrointest Endosc. 2009; 70: 402‒403.