Abstract
Syzygium cumini is used worldwide for the treatment of metabolic syndrome-associated outcomes. Previously, we described the antihypertriglyceridemic effect of the hydroethanolic extract of S. cumini leaf (HESc) in monosodium L-glutamate- (MSG-) induced obese rats. This study sought to investigate the molecular mechanisms underlying the antihypertriglyceridemic effect of HESc in MSG-obese rats. Newborn male Wistar rats were injected subcutaneously with MSG (4.0 g/kg/day, obese group) or saline 1.25% (1.0 mL/kg/day, lean group), from 2nd through 10th postnatal day. At 8 weeks old, obese rats started to be orally treated with HESc (0.5 or 1.0 g/kg/day, n = 7) or saline 0.9% (1 mL/kg/day, n = 7). Lean rats received saline solution (1 mL/kg/day, n = 7). Upon 8-week treatment, animals were euthanized for blood and tissue collection. Another set of adult nonobese Wistar rats was used for the assessment of HESc acute effects on Triton WR1339-induced hypertriglyceridemia. HESc reduced weight gain, as well as adipose tissue fat pads, without altering food intake of obese rats. HESc restored fasting serum glucose, triglycerides, total cholesterol, and free fatty acids, as well as insulin sensitivity, to levels similar to lean rats. Additionally, HESc halved the triglyceride content into very low-density lipoprotein particles, as well as healed liver steatosis, in obese rats. Hepatic protein expression of the endoplasmic reticulum chaperone GRP94 was decreased by HESc, which also downregulated the hepatic triglyceride secretion pathway by reducing the splicing of X-box binding protein 1 (XBP-1s), as well as protein disulfide isomerase (PDI) and microsomal triglyceride transfer protein (MTP) translational levels. This action was further corroborated by the acute inhibitory effect of HESc on triglyceride accumulation on Triton WR1339-treated rats. Our data support the downregulation of the XBP-1s/PDI/MTP axis in the liver of MSG-obese rats as a novel feasible mechanism for the antihypertriglyceridemic effect promoted by the polyphenolic phytocomplex present in S. cumini leaf.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is considered the main hepatic manifestation of metabolic syndrome (MetS)[1]
Hyperinsulinemia imposes de novo lipogenesis oversizing hepatic fat accumulation, an outcome partially compensated by increased triglyceride (TG) secretion via very low-density lipoprotein (VLDL) particles, that leads to hypertriglyceridemia [3]
Studies conducted by us [8] and others [9,10,11] have demonstrated the importance of the IRE1α/XBP-1 protein expression for both spliced (XBP-1s) pathway for hepatic lipid homeostasis, through either lipogenesis modulation or stimulation of TG secretion, a process mediated by upregulation of microsomal triglyceride transfer protein (MTP) and protein disulfide isomerase (PDI) expression in hepatocytes [8]
Summary
Nonalcoholic fatty liver disease (NAFLD) is considered the main hepatic manifestation of metabolic syndrome (MetS)[1]. Hyperinsulinemia imposes de novo lipogenesis oversizing hepatic fat accumulation, an outcome partially compensated by increased triglyceride (TG) secretion via very low-density lipoprotein (VLDL) particles, that leads to hypertriglyceridemia [3]. IRE-1α subsequently splices the X-box binding protein 1 (XBP-1s) mRNA, a transcription factor importantly involved in the reestablishment of ER homeostasis [6] and hepatic lipogenesis regulation [7]. Studies conducted by us [8] and others [9,10,11] have demonstrated the importance of the IRE1α/XBP-1s pathway for hepatic lipid homeostasis, through either lipogenesis modulation or stimulation of TG secretion, a process mediated by upregulation of microsomal triglyceride transfer protein (MTP) and protein disulfide isomerase (PDI) expression in hepatocytes [8]. The XBP-1s/PDI/MTP axis has emerged as a potential therapeutic target for the treatment of lipid metabolism disorders, especially hypertriglyceridemia [12], despite the plethora of other regulatory targets
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
