Plant-Derived (Poly)phenols and Their Metabolic Outcomes: The Pursuit of a Role for the Gut Microbiota.

Plant-derived (poly)phenolic compounds have been undoubtedly shown to promote endocrine homeostasis through the improvement of diverse metabolic outcomes. Amongst diverse potential mechanisms, the prebiotic modulatory effects exerted by these compounds on the gut microbiota have supported their nutraceutical application in both experimental and clinical approaches. However, the comprehension of the microbiota modulatory patterns observed upon (poly)phenol-based dietary interventions is still in its infancy, which makes the standardization of the metabolic outcomes in response to a given (poly)phenol a herculean task. Thus, this narrative review sought to gather up-to-date information on the relationship among (poly)phenols intake, their modulatory effect on the gut microbiota diversity, and consequent metabolic outcomes as a supportive tool for the future design of experimental approaches and even clinical trials.

Plant Metabolites as SARS-CoV-2 Inhibitors Candidates: In Silico and In Vitro Studies.

Since it acquired pandemic status, SARS-CoV-2 has been causing all kinds of damage all over the world. More than 6.3 million people have died, and many cases of sequelae are in survivors. Currently, the only products available to most of the world's population to fight the pandemic are vaccines, which still need improvement since the number of new cases, admissions into intensive care units, and deaths are again reaching worrying rates, which makes it essential to compounds that can be used during infection, reducing the impacts of the disease. Plant metabolites are recognized sources of diverse biological activities and are the safest way to research anti-SARS-CoV-2 compounds. The present study computationally evaluated 55 plant compounds in five SARS-CoV-2 targets such Main Protease (Mpro or 3CL or MainPro), RNA-dependent RNA polymerase (RdRp), Papain-Like Protease (PLpro), NSP15 Endoribonuclease, Spike Protein (Protein S or Spro) and human Angiotensin-converting enzyme 2 (ACE-2) followed by in vitro evaluation of their potential for the inhibition of the interaction of the SARS-CoV-2 Spro with human ACE-2. The in silico results indicated that, in general, amentoflavone, 7-O-galloylquercetin, kaempferitrin, and gallagic acid were the compounds with the strongest electronic interaction parameters with the selected targets. Through the data obtained, we can demonstrate that although the indication of individual interaction of plant metabolites with both Spro and ACE-2, the metabolites evaluated were not able to inhibit the interaction between these two structures in the in vitro test. Despite this, these molecules still must be considered in the research of therapeutic agents for treatment of patients affected by COVID-19 since the activity on other targets and influence on the dynamics of viral infection during the interaction Spro x ACE-2 should be investigated.

Prebiotic effects of plant-derived (poly)phenols on host metabolism: Is there a role for short-chain fatty acids?

The gut microbiota has been extensively investigated during the last decade because of its effects on host neuroendocrine pathways and other processes. The imbalance between beneficial and pathogenic bacteria, known as dysbiosis, may be a determining predisposing factor for many noncommunicable chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, and Alzheimer's disease. On the other hand, interventions aiming to reestablish the balance between microbiota components have been suggested as potential preventive therapeutic strategies against these disorders. Among these interventions, dietary supplementation with (poly)phenols has been highlighted due to the modulatory effects exerted by those compounds on the gut microbiota. In addition, (poly)phenol consumption is associated with increased production of short-chain fatty acids (SCFAs), a set of microbial metabolites whose actions are ascribed to improving the abovementioned metabolic disorders. Thus, this review discusses the modulation of the gut microbiota by prebiotic (poly)phenols based on in vivo studies performed with isolated (poly)phenolic compounds, their interaction with the gut microbiota and the production of SCFAs in pursuit of the molecular mechanisms underlying the health effects of (poly)phenols on host metabolism.

Hippocampal Endoplasmic Reticulum Stress Hastens Motor and Cognitive Decline in Adult Male Rats Sustainedly Exposed to High-Sucrose Diet.

Metabolic dysfunctions, such as hyperglycemia and insulin resistance, have been associated to cognitive impairment and dementia regardless of advanced age, although the underlying mechanisms are still elusive. Thus, this study investigates the deleterious effects of metabolic syndrome (MetS) induced by long-term exposure to a high-sucrose diet on motor and cognitive functions of male adult rats and its relationship with hippocampal endoplasmic reticulum (ER) stress. Weaned Wistar male rats were fed a high-sucrose diet until adulthood (HSD; 6 months old) and compared to both age-matched (CTR; 6 months old) and middle-aged chow-fed rats (OLD; 20 months old). MetS development, serum redox profile, behavioral, motor, and cognitive functions, and hippocampal gene/protein expressions for ER stress pro-adaptive and pro-apoptotic pathways, as well as senescence markers were assessed. Prolonged exposure to HSD induced MetS hallmarked by body weight gain associated to central obesity, hypertriglyceridemia, insulin resistance, and oxidative stress. Furthermore, HSD rats showed motor and cognitive decline similar to that in OLD animals. Noteworthy, HSD rats presented marked hippocampal ER stress characterized by failure of pro-adaptive signaling and increased expression of Chop, p21, and Parp-1 cleavage, markers of cell death and aging. This panorama resembles that found in OLD rats. In toto, our data showed that early and sustained exposure to a high-sucrose diet induced MetS, which subsequently led to hippocampus homeostasis disruption and premature impairment of motor and cognitive functions in adult rats.

Myricetin improves metabolic outcomes but not cognitive deficit associated to metabolic syndrome in male mice.

Myricetin is a flavonol highly prevalent in edible vegetables and fruits, with recognized hypoglycemic and anti-obesity effects, besides great antioxidant capacity. Thus, this study sought to investigate whether myricetin is able to improve metabolic and behavioral outcomes found in monosodium l-glutamate (MSG) obese mice, a model of metabolic syndrome characterized by early hyperinsulinemia associated to obesity, dyslipidemia, hepatic steatosis, anxiety and cognitive deficit. Newborn male mice received MSG (4 mg kg-1 day-1, s.c.) on alternate days during the first 10 days of life for obesity induction, while control pups received equimolar saline solution. From postnatal day 90 to 135, MSG mice were orally treated with myricetin (50 mg kg-1 day-1) or distilled water, while control animals received vehicle. During the last week of treatment, all groups were submitted to behavioral tests: open field maze, elevated plus maze and Morris water maze. At the end of treatment, animals were euthanized for collection of liver, serum and adipose tissue fat pads. Myricetin treatment reduced the elevated serum levels of glucose and triglycerides, typically found in MSG mice, as well as restored peripheral insulin sensitivity and liver steatosis. Moreover, myricetin ameliorated the lack of thigmotaxis and exploratory behavior, but did not improve the cognitive deficit presented by MSG mice. Therefore, this study contributes to the pharmacological validation of myricetin as an affordable and healthy therapeutic adjuvant for the treatment of metabolic syndrome and most of its comorbidities.

Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) particularly among chronic consumers of added sugar-rich diets. However, the impact of early consumption of such diets on NAFLD onset and progression is unclear. Thus, this study sought to characterise metabolic factors involved in NAFLD progression in young mice fed with a high-sucrose diet (HSD). Male Swiss mice were fed HSD or regular chow (CTR) from weaning for up to 60 or 90 days. Obesity development, glucose homeostasis and serum biochemical parameters were determined at each time-point. At day 90, mice were euthanised and white adipose tissue (WAT) collected for lipolytic function assessment and liver for histology, gene expression and cytokines quantification. At day 60, HSD mice presented increased body mass, hypertriglyceridemia, peripheral insulin resistance (IR) and simple steatosis. Upon 90 days on diet, WAT from HSD mice displayed impaired insulin sensitivity, which coincided with increased fasting levels of glucose and free fatty acids (FFA), as well as NAFLD progression to NASH. Transcriptional levels of lipogenic genes, particularly stearoyl-CoA desaturase-1, were consistently increased, leading to hepatic leukocyte infiltration and pro-inflammatory cytokines spillover. Therefore, our dataset supports IR triggering in the WAT as a major factor for dysfunctional release of FFA towards portal circulation and consequent upregulation of lipogenic genes and hepatic inflammatory onset, which decisively concurred for NAFLD-to-NASH progression in young HSD-fed mice. Notwithstanding, this study forewarns against the early introduction of dietary sugars in infant diet, particularly following breastfeeding cessation.

Unfolded Protein Response: Cause or Consequence of Lipid and Lipoprotein Metabolism Disturbances?

The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?

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

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.

Long-term exposure to high-sucrose diet down-regulates hepatic endoplasmic reticulum-stress adaptive pathways and potentiates de novo lipogenesis in weaned male mice.

Childhood consumption of added sugars, such as sucrose, has been associated to increased risk of metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Although the mechanisms underlying NAFLD onset are incompletely defined, recent evidence has proposed a role for the endoplasmic reticulum (ER) stress. Thus, the present study sought to investigate the metabolic outcomes of high-sucrose intake on weaned Swiss mice fed a 25% sucrose diet for 30, 60 and 90 days in comparison to regular chow-fed controls. High-sucrose feeding promoted progressive metabolic and oxidative disturbances, starting from fasting and fed hyperglycemia, hyperinsulinemia, glucose intolerance and increased adiposity at 30-days; passing by insulin resistance, hypertriglyceridemia and NAFLD onset at 60 days; until late hepatic oxidative damage at 90 days. In parallel, assessment of transcriptional and/or translational levels of de novo lipogenesis (DNL) and ER stress markers showed up-regulation of both fatty acid synthesis (ChREBP and SCD1) and oxidation (PPARα and CPT-1α), as well as overexpression of unfolded protein response sensors (IRE1α, PERK and ATF6), chaperones (GRP78 and PDIA1) and antioxidant defense (NRF2) genes at 30 days. At 60 days, fatty acid oxidation genes were down-regulated, and ER stress switched over toward a proapoptotic pattern via up-regulation of BAK protein and CHOP gene levels. Finally, down-regulation of both NRF2 and CPT-1α protein levels led to late up-regulation of SREBP-1c and exponential raise of fatty acids synthesis. In conclusion, our study originally demonstrates a temporal relationship between DNL and ER stress pathways toward MetS and NAFLD development on weaned rats fed a high-sucrose diet.

Western diet triggers Toll-like receptor 4 signaling-induced endothelial dysfunction in female Wistar rats.

Overconsumption of a diet rich in fat and carbohydrates, called the Western diet, is a major contributor to the global epidemic of cardiovascular disease. Despite previously documented cardiovascular protection exhibited in female rats, this safeguard may be lost under certain metabolic stressors. We hypothesized that female Wistar rats challenged by a Western diet composed of 21% fat and 50% carbohydrate (34.1% sucrose) for 17 wk would develop endothelial dysfunction via endothelial Toll-like receptor 4 (TLR4) signaling. Western diet-fed female rats exhibited dysregulation of metabolism, revealing increased body weight and abdominal fat, decreased expression of adiponectin in white adipose tissue, glucose intolerance, and impaired insulin sensitivity. Western diet exposure increased hepatic triglycerides and cholesterol alongside hepatic steatosis, categorizing nonalcoholic fatty liver disease. Moreover, a Western diet negatively affected vascular function, revealing hypertension, impaired endothelium-dependent vasorelaxation, aortic remodeling, and increased reactive oxygen species (ROS) production. Aortic protein expression of TLR4 and its downstream proteins were markedly increased in the Western diet-fed group in association with elevated serum levels of free fatty acids. In vitro experiments were conducted to test whether free fatty acids contribute to vascular ROS overproduction via the TLR4 signaling pathway. Cultured endothelial cells were stimulated with palmitate in the presence of TAK-242, a TLR4 signaling inhibitor. Palmitate-induced overgeneration of ROS in endothelial cells was abolished in the presence of TAK-242. Our data show that a Western diet induced endothelial dysfunction in female rats and suggest that endothelial TLR4 signaling may play a key role in abolishing female cardiovascular protection. NEW & NOTEWORTHY A Western diet induced elevated levels of free fatty acids, produced nonalcoholic fatty liver disease, and provoked endothelial dysfunction in female rats in association with Toll-like receptor 4 signaling-mediated vascular reactive oxygen species production. Limited consumption of a Western diet in premenopausal women may decrease their risk of cardiovascular complications.

Long-term high-protein diet intake reverts weight gain and attenuates metabolic dysfunction on high-sucrose-fed adult rats.

BACKGROUND: Consumption of added sugars has been considered a worldwide public health concern by its association with metabolic syndrome and its comorbidities. Meanwhile, current studies have suggested high-protein diets to promote weight loss and improved metabolic outcomes. Thus, this study aimed to investigate the effects of long-term high-protein diet (HPD, 34.3% protein) intake on high-sucrose-fed rats. METHODS: Weaned male Wistar rats were randomized into two groups: rats fed a standard chow (CT/CT, 10% sucrose) or rats fed a high-sucrose diet (HSD, 25% sucrose) for a 20-week observational period. Subsequently, HS/HS animals were randomized into 3 new groups: rats maintained on HSD diet (HS/HS); rats submitted to HSD replacement by standard chow (HS/CT); and those with HSD replaced by HPD (HS/HP). All groups were followed up for 12 weeks during which we investigated the effects of HPD on body weight, energy intake, obesity development, glicemic/lipid profile, glucose tolerance, insulin resistance, tissue weight (adipose tissue, liver and skeletal muscles), lipolytic activity, liver lipoperoxidation and histology, as well as serum markers of hepatic function. RESULTS: Post-weaning exposure to HSD led to metabolic syndrome phenotype at adulthood, herein characterized by central obesity, glucose intolerance, dyslipidaemia and insulin resistance. Only HPD feeding was able to revert weight gain and adipose tissue accumulation, as well as restore adipose tissue lipolytic response to sympathetic stimulus. On the other hand, either HPD or withdrawal from HSD promoted very similar metabolic outcomes upon 12-week nutritional intervention. HS/HP and HS/CT rats showed reduced fasting serum levels of glucose, triacylglycerol and total cholesterol, which were correlated with the improvement of peripheral insulin sensitivity, as inferred from kITT and TyG Index values. Both nutritional interventions restored liver morphofunctional patterns, but only HPD restored lipid peroxidation. CONCLUSIONS: Our data showed that 12-week intake of an isocaloric moderately high-protein diet consistently restored high-sucrose-induced central adiposity and obesity in addition to the attenuation of other important metabolic outcomes, such as improvement of glucolipid homeostasis associated to increased insulin sensitivity and reversal of hepatic steatosis. On the other hand, simple withdrawal from high-sucrose consumption also promoted the abovementioned metabolic outcomes with no impact on body weight.

Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats.

Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47-phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF-α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM.

Early and sustained exposure to high-sucrose diet triggers hippocampal ER stress in young rats.

Early-life environmental insults have been shown to promote long-term development of chronic non-communicable diseases, including metabolic disturbances and mental illnesses. As such, premature consumption of high-sugar foods has been associated to early onset of detrimental outcomes, whereas underlying mechanisms are still poorly understood. In the present study, we sought to investigate whether early and sustained exposure to high-sucrose diet promotes metabolic disturbances that ultimately might anticipate neurological injuries. At postnatal day 21, weaned male rats started to be fed a standard chow (10 % sucrose, CTR) or a high-sucrose diet (25 % sucrose, HSD) for 9 weeks prior to euthanasia at postnatal day 90. HSD did not alter weight gain and feed efficiency between groups, but increased visceral, non-visceral and brown adipose tissue accumulation. HSD rats demonstrated elevated blood glucose levels in both fasting and fed states, which were associated to impaired glucose tolerance. Peripheral insulin sensitivity did not change, whereas hepatic insulin resistance was supported by increased serum triglyceride levels, as well as higher TyG index values. Assessment of hippocampal gene expression showed endoplasmic reticulum (ER) stress pathways were activated in HSD rats, as compared to CTR. HSD rats had overexpression of unfolded protein response sensors, PERK and ATF6; ER chaperone, PDIA2 and apoptosis-related genes, CHOP and Caspase 3; but decreased expression of chaperone GRP78. Finally, HSD rats demonstrated impaired neuromuscular function and anxious behavior, but preserved cognitive parameters. In conclusion, our data indicate that early exposure to HSD promote metabolic disturbances, which disrupt hippocampus homeostasis and might precociously affect its neurobehavioral functions.

Reproductive alterations in hyperinsulinemic but normoandrogenic MSG obese female rats.

Obesity and metabolic syndrome are the common causes of reproductive and fertility disorders in women. In particular, polycystic ovary syndrome, which is clinically characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, has been increasingly associated with metabolic disorders. However, given the broad interplay between metabolic and reproductive functions, this remains a field of intense research. In this study, we investigated the effect of monosodium l-glutamate (MSG)-induced obesity on reproductive biology of female rats. Newborn female rats were subcutaneously injected with MSG (4g/kg/day) or equiosmolar saline (CTR) each 2 days up to postnatal day (pnd) 10. On pnd 60, estrous cycle was evaluated using vaginal smears twice a day for 15 days, which showed MSG rats to be oligocyclic. Thereafter, animals were killed on estrous phase for blood and tissue collection. MSG rats had increased body mass, accumulation of retroperitoneal and visceral fat pads, and visceral adipocyte hypertrophy compared with CTR rats. MSG rats were also dyslipidemic and hyperinsulinemic but were normoglycemic and normoandrogenic. Ovarian morphology analysis showed that MSG rats had a two-fold decrease in oocyte count but a six-fold increase on ovarian follicular cysts, along with a higher number of total primordial and atretic follicles. Moreover, MSG rats had a four-fold increase in anti-Müllerian hormone immunohistochemical staining on antral follicles. Taken together, data presented here characterize MSG obesity as a unique model to study the metabolic pathways underlying reproductive disorders in the absence of overactivated hypothalamic-pituitary-gonadal axis.

Syzygium cumini (L.) skeels: a prominent source of bioactive molecules against cardiometabolic diseases.

Syzygium cumini (Myrtaceae) is a worldwide medicinal plant traditionally used in herbal medicines due to its vaunted properties against cardiometabolic disorders, which include: antihyperglycemic, hypolipemiant, antiinflammatory, cardioprotective, and antioxidant activities. These properties have been attributed to the presence of bioactive compounds such as phenols, flavonoids, and tannins in different parts of the plant, albeit the knowledge on their mechanisms of action is scarce. This mini-review highlights the cardiometabolic properties of S. cumini by correlating its already identified phytochemicals with their described mechanisms of action. Data herein compiled show that some compounds target multiple metabolic pathways; thereby, becoming potential pharmacological tools. Moreover, the lack of clinical trials on S. cumini usage makes it a fruitful field of interest for both scientific community and pharmaceutical industry.

Mechanisms underlying hypertriglyceridemia in rats with monosodium L-glutamate-induced obesity: evidence of XBP-1/PDI/MTP axis activation.

Non-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium L-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression.