Syzygium cumini Leaf Extract Reverts Hypertriglyceridemia via Downregulation of the Hepatic XBP-1s/PDI/MTP Axis in Monosodium L-Glutamate-Induced Obese Rats

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.

Pediococcus pentosaceus PP04 Ameliorates High-Fat Diet-Induced Hyperlipidemia by Regulating Lipid Metabolism in C57BL/6N Mice

“…CPT1 stimulates the uptake of fat and mitochondrial fatty acid oxidation, and PPARα can regulate the β-oxidation of fatty acids by upregulating CPT1 to prevent excessive lipid accumulation in the liver . On the other hand, p-AMPK enhances fatty acid oxidation by increasing PPARα expression . MTP is a lipid transfer protein that transfers TG from hepatocytes to apolipoprotein B (ApoB) .…”

“…47 On the other hand, p-AMPK enhances fatty acid oxidation by increasing PPARα expression. 48 MTP is a lipid transfer protein that transfers TG from hepatocytes to apolipoprotein B (ApoB). 49 Because of the increased level of p-AMPK after PP04 administration, the protein expression levels of PPARα, CPT1, and MTP were enhanced drastically (Figure 5D).…”

Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease

“…ApoB100 and microsomal TG transfer protein (MTP) mediate VLDL secretion in hepatocytes. Studies have revealed that pharmacological inhibition of MTP can be used to treat hyperlipidaemia in rats with monosodium L-glutamate-induced obesity, while increases in MPT gene or protein expression can be used to treat NAFLD [33][34][35]. Studies have also indicated that upregulating PPAR-α, carnitine palmitoyltransferase-1a (CPT-1a) and fatty TG lipase (ATGL) to enhance FA oxidation and lipolysis can improve NAFLD in micee [36,37].…”

Antidiabetic activity and acute toxicity of combined extract of Andrographis paniculata, Syzygium cumini, and Caesalpinia sappan

“…Andrographolide, the main bioactive chemical constituent of A. paniculata , has been reported to have antidiabetic potential ( Yu et al., 2008 ; Zhang et al., 2009 ; Sari et al., 2015 ). S. cumini is a native Indian tree that is widespread around the world and is also used as an antidiabetic ( Chagas et al., 2018 ; França et al., 2019 ). In Indonesia, the tree is referred to as Jamblang.…”