Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.

High-protein high-konjac glucomannan diets changed glucose and lipid metabolism by modulating colonic microflora and bile acid profiles in healthy mouse models.

High protein and fiber diets are becoming increasingly popular for weight loss; however, the benefits or risks of high protein and fiber diets with a normal calorie level for healthy individuals still need to be elucidated. In this study, we explored the role and mechanisms of long-term high protein and/or konjac glucomannan diets on the metabolic health of healthy mouse models. We found that high konjac glucomannan contents improved the glucose tolerance of mice and both high protein and high konjac glucomannan contents improved the serum lipid profile but increased the TNF-α levels. In the liver, high dietary protein contents reduced the expression of the FASN gene related to fatty acid synthesis. Interactions of dietary protein and fiber were shown in the signaling pathways related to lipid and glucose metabolism of the liver and the inflammatory status of the colon, wherein the high protein and high konjac glucomannan diet downregulated the expression of the SREBF1 and FXR genes in the liver and downregulated the expression of TNF-α genes in the colon compared to the high protein diet. High konjac glucomannan contents reduced the colonic secondary bile acid levels including DCA and LCA; this was largely associated with the changed microbiota profile and also contributed to improved lipid and glucose homeostasis. In conclusion, high protein diets improved lipid homeostasis and were not a risk to metabolic health, while high fiber diets improved glucose and lipid homeostasis by modulating colonic microbiota and bile acid profiles, and a high protein diet supplemented with konjac glucomannan might improve hepatic lipid homeostasis and colonic inflammation in healthy mouse models through long-term intervention.

Lacticaseibacillus rhamnosus HF01 fermented yogurt alleviated high-fat diet-induced obesity and hepatic steatosis via the gut microbiota-butyric acid-hepatic lipid metabolism axis.

The objective of this study was to investigate the anti-obesity effects and underlying mechanism of Lacticaseibacillus rhamnosus HF01 fermented yogurt (HF01-Y). Herein, obesity was induced in mice through a high-fat diet and the changes in the gut microbiota were evaluated using 16S rRNA gene sequencing, combined with the expression levels of the liver AMPK signaling pathway to analyze the potential relationship between HF01-Y-mediated gut microbiota and obesity. The results showed that supplementation with HF01-Y improved obesity-related phenotypes in mice, including reduced body weight, improved serum lipid profiles, and decreased hepatic lipid droplet formation. In addition, HF01-Y altered the composition of the gut microbiota in obese mice, significantly upregulated norank_f__Muribaculaceae, unclassified_c__Clostridia, Blautia, unclassified_o__Bacteroidales, and Rikenellaceae_RC9_gut_group, while downregulating unclassified_f__Desulfovibrionaceae, Colidextribacter, and unclassified_f__Oscillospiraceae. These alterations led to an increase of the cecum butyric acid content, which in turn indirectly promoted the activation of the AMPK signaling pathway, subsequently, inhibited fat synthesis, and promoted fatty acid oxidation related gene expression. Therefore, HF01-Y was likely to alleviate hepatic fat and relieve obesity by modulating the gut microbiota-butyric acid-hepatic lipid metabolism axis, ultimately promoting host health.

Maternal PFOS exposure in mice induces hepatic lipid accumulation and inflammation in adult female offspring: Involvement of microbiome-gut-liver axis and autophagy.

Perfluorooctane sulfonates (PFOS) are the persistent organic pollutants. In the present study, 0, 0.3, or 3-mg/kg PFOS were administered to pregnant mice from GD 11 to GD 18. The histopathology of liver and intestine, serum and hepatic lipid levels, lipid metabolism related genes, and gut microbiota were examined in adult female offspring. The results suggested that maternal PFOS exposure increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and induced F4/80+ macrophage infiltration in adult female offspring, in addition to the elevation of TNF-α and IL-1ß mRNA levels in low-dose and high-dose groups, respectively. Furthermore, maternal exposure to PFOS increased serum triglyceride (TG) and hepatic total cholesterol (TC) levels, which was associated with the alteration of the process of fatty acid transport and ß-oxidation, TG synthesis and transport, cholesterol synthesis and excretion in the liver. The AMPK/mTOR/autophagy signaling was also inhibited in the liver of adult female offspring. Moreover, changes in gut microbiota were also related to lipid metabolism, especially for the Desulfovibrio, Ligilactobacillus, Enterorhabdus, HT002 and Peptococcaceae_unclassified. Additionally, maternal exposure to PFOS decreased mRNA expressions of the tight junction protein and AB+ goblet cells in the colon, while increasing the overproduction of lipopolysaccharides (LPS) and F4/80+ macrophage infiltration. Collectively, maternal PFOS exposure induced liver lipid accumulation and inflammation, which strongly correlated with the disruption of the gut-liver axis and autophagy in adult female offspring, highlighting the persistent adverse effects in offspring exposed to PFOS.

Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.

Low beauvericin concentrations promote PC-12 cell survival under oxidative stress by regulating lipid metabolism and PI3K/AKT/mTOR signaling.

Beauvericin (BEA), a naturally occurring cyclic peptide with good pharmacological activity, has been widely explored in anticancer research. Although BEA is toxic, studies have demonstrated its antioxidant activity. However, to date, the antioxidant mechanisms of BEA remain unclear. Herein, we conducted a comprehensive and detailed study of the antioxidant mechanism of BEA using an untargeted metabolomics approach, subsequently validating the results. BEA concentrations of 0.5 and 1 µM significantly inhibited H2O2-induced oxidative stress (OS), decreased reactive oxygen species levels in PC-12 cells, and restored the mitochondrial membrane potential. Untargeted metabolomics indicated that BEA was primarily involved in lipid-related metabolism, suggesting its role in resisting OS in PC-12 cells by participating in lipid metabolism. BEA combated OS damage by increasing phosphatidylcholine, phosphatidylethanolamine, and sphingolipid levels. In the current study, BEA upregulated proteins related to the PI3K/AKT/mTOR pathway, thereby promoting cell survival. These findings support the antioxidant activity of BEA at low concentrations, warranting further research into its pharmacological effects.

Pharmaceutical Food Science: Search for Bio-Functional Molecules Obtained from Natural Resources to Prevent and Ameliorate Lifestyle Diseases.

In this review, our resent pharmaceutical food science research for bio-functional molecules obtained from natural resources that contribute to i) suppression of postprandial blood glucose elevation and/or improvement of glucose tolerance and ii) reduction of visceral fat accumulation and improvement of lipid metabolism were summarized. Based on studies using MONOTORI science, salacinol (1), neokotalanol (4), and trans-tiliroside (20) have been approved or notified by the Consumer Affairs Agency in Japan as functional substances in food with health claims, Food for Specified Health Use and Food with Functional Claims.

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Resveratrol reverses Palmitic Acid-induced cow neutrophils apoptosis through shifting glucose metabolism into lipid metabolism via Cav-1/ CPT 1-mediated FAO enhancement.

Elevated plasma nonesterified fatty acids (NEFAs) affect neutrophils function and longevity during the periparturient period in dairy cows. Previous research has shown that resveratrol (RSV) may protect cell viability from NEFA-induced damage by regulating energy metabolism. However, it is unclear whether RSV has a protective effect on palmitic acid (PA)-treated neutrophils. The aim of this study was to investigate the molecular regulatory mechanism of the protective effect of RSV on neutrophils. The results showed that treatment with high concentrations of RSV (50 µM, 100 µM) maintained neutrophils activity by inhibiting neutrophils apoptosis (P < 0.05). Further analysis showed that high concentrations of RSV enhanced fatty acid oxidation (FAO) to produce ATP by promoting the expression of CAV1, ACSL-1 and CPT1 (P < 0. 05) while inhibiting glycolysis by suppressing PFK1 activity (P < 0. 05) and reducing glucose transport-related protein (GLUT1/GLUT4) expression by inhibiting glucose uptake (P < 0.05). These results suggest that RSV protects neutrophils from PA-induced apoptosis by regulating energy metabolism. Our results revealed that RSV protects neutrophils from PA-induced apoptosis by shifting glucose metabolism to lipid metabolism. This study tenders to a meaningful understanding of the effects of RSV on neutrophils function in periparturient cows suffering from negative energy balance (NEB).

A comprehensive insight into the molecular effect of theobromine on cardiovascular-related risk factors: A systematic review of in vitro and in vivo studies.

Theobromine may have beneficial effects on cardiovascular risk factors. This study aimed to find molecular effects of theobromine on lipid profile, glycemic status, inflammatory factors, and vascular function through a comprehensive assessment of all in vitro and in vivo studies. The search process was started at 18 July 2022. Databases including PubMed, Scopus, and Web of Science were searched to find all articles published up to 18 July 2022. Nineteen studies were included in this study. In vitro studies showed the improving effects of theobromine on inflammatory markers. Of four animal studies assessing the effect of theobromine on inflammatory markers, two reported favorable effects. Among five animal studies assessing the effects of theobromine on lipid profile, three reported improving effects on either triglyceride, total cholesterol, low- or high-density lipoprotein cholesterol. Of the three human studies, two revealed that theobromine had improving effects on lipid profile. A favorable effect of theobromine on augmentation index was also reported in two RCTs. The results for other outcomes were inconclusive. Theobromine may have favorable effects on inflammatory factors, lipid profile, and vascular function markers. However, studies with a longer duration and lower, dietary-relevant doses are required for future confirmation.

Exposure to 6-PPD quinone enhances lipid accumulation through activating metabolic sensors of SBP-1 and MDT-15 in Caenorhabditis elegans.

Although it has been shown that exposure to 6-PPDQ can cause toxicity on environmental organisms, its possible effects on metabolic state remain largely unclear. We here determined the effect of 6-PPDQ exposure on lipid accumulation in Caenorhabditis elegans. We observed increase in triglyceride content, enhancement in lipid accumulation, and increase in size of lipid droplets in 6-PPDQ (1-10 µg/L) exposed nematodes. This detected lipid accumulation was associated with both increase in fatty acid synthesis reflected by increased expressions of fasn-1 and pod-2 and inhibition in mitochondrial and peroxisomal fatty acid ß-oxidation indicated by decreased expressions of acs-2, ech-2, acs-1, and ech-3. The observed lipid accumulation in 6-PPDQ (1-10 µg/L) exposed nematodes was also related to the increase in synthesis of monounsaturated fatty acylCoAs reflected by altered expressions of fat-5, fat-6, and fat-7. Exposure to 6-PPDQ (1-10 µg/L) further increased expressions of sbp-1 and mdt-15 encoding two metabolic sensors to initiate the lipid accumulation and to regulate the lipid metabolism. Moreover, the observed increase in triglyceride content, enhancement in lipid accumulation, and alterations in fasn-1, pod-2, acs-2, and fat-5 expressions in 6-PPDQ exposed nematodes were obviously inhibited by sbp-1 and mdt-15 RNAi. Our observations demonstrated the risk of 6-PPDQ at environmentally relevant concentration in affecting lipid metabolic state in organisms.

Naphthofuran Derivative BF4, a New Potent SIRT1 Activator, Regulates Lipid Metabolism in 3T3-L1 Adipocytes via the SIRT1-AMPK Pathway.

AIM: Our previously reported naphthofuran derivative BF4, identified as a potent silent information regulator 1 (SIRT1) activator, could alleviate high glucose stimulating apoptosis and inflammation response in human renal tubular epithelial (HK-2) cells. INTRODUCTION: In this study, the underlying effects of BF4 on lipid metabolism in 3T3-L1 adipocytes were investigated. METHODS: The effects of BF4 on pre-adipocyte differentiation and adipocyte lipolysis were studied using oil red O staining and quantitative glycerol and triglyceride content assay kits. Moreover, the molecular mechanism of BF4 on adipogenesis and lipid metabolism in 3T3-L1 adipocytes was investigated by real-time quantitative PCR and Western blotting analysis. RESULTS: We found that compound BF4 significantly decreased adipogenesis and lipid accumulation and inhibited the differentiation of 3T3-L1 pre-adipocytes into adipocytes. Moreover, compound BF4 decreased the expressions of several key regulators in adipocyte differentiation, including C/EBPß and PPARγ, and their downstream lipogenesis targets via the activation of the SIRT1/ AMPK pathway. CONCLUSION: Our results demonstrated that the novel SIRT1 activator BF4 might be a potent candidate for regulating lipid metabolism.

Inhibitory Effect of Styrylpyrone Extract of Phellinus linteus on Hepatic Steatosis in HepG2 Cells.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be approximately about 25.24% of the population worldwide. NAFLD is a complex syndrome and is characterized by a simple benign hepatocyte steatosis to more severe steatohepatitis in the liver pathology. Phellinus linteus (PL) is traditionally used as a hepatoprotective supplement. Styrylpyrone-enriched extract (SPEE) obtained from the PL mycelia has been shown to have potential inhibition effects on high-fat- and high-fructose-diet-induced NAFLD. In the continuous study, we aimed to explore the inhibitory effects of SPEE on free fatty acid mixture O/P [oleic acid (OA): palmitic acid (PA); 2:1, molar ratio]-induced lipid accumulation in HepG2 cells. Results showed that SPEE presented the highest free radical scavenging ability on DPPH and ABTS, and reducing power on ferric ions, better than that of partitions obtained from n-hexane, n-butanol and distilled water. In free-fatty-acid-induced lipid accumulation in HepG2 cells, SPEE showed an inhibition effect on O/P-induced lipid accumulation of 27% at a dosage of 500 µg/mL. As compared to the O/P induction group, the antioxidant activities of superoxide dismutase, glutathione peroxidase and catalase were enhanced by 73%, 67% and 35%, respectively, in the SPEE group. In addition, the inflammatory factors (TNF-α, IL-6 and IL-1ß) were significantly down-regulated by the SPEE treatment. The expressions of anti-adipogenic genes involved in hepatic lipid metabolism of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were enhanced in the SPEE supplemented HepG2 cells. In the protein expression study, p-AMPK, SIRT1 and PGC1-α were significantly increased to 121, 72 and 62%, respectively, after the treatment of SPEE. Conclusively, the styrylpyrone-enriched extract SPEE can ameliorate lipid accumulation and decrease inflammation and oxidative stress through the activation of SIRT1/AMPK/PGC1-α pathways.

Cinnamaldehyde affects lipid droplets metabolism after adipogenic differentiation of C2C12 cells.

BACKGROUND: Based on our previous research conducted on cinnamaldehyde (CA) exhibiting its ability to improve the growth performance of fattening pigs and the adipogenesis induction model of C2C12 cells constructed in our laboratory, we explored the effects of CA on the generation and development of lipid droplets (LDs) in adipogenic differentiated C2C12 cells. METHODS AND RESULTS: C2C12 cells were treated with either 0.4 mM or 0.8 mM CA. BODIPY staining and triglyceride measurements were conducted to observe the morphology of LDs, and Western blotting was used to measure the expression of their metabolism-related proteins. The results showed that the average number of LDs in the CA treatment groups was more than the control group (P < 0.05), whereas the average LD size and triglyceride content decreased (P < 0.05). Compared with the control group, the expression levels of fusion-related genes in the LDs of the CA treatment group significantly decreased, while decomposition-related genes and autophagy-related genes in the LDs in C2C12 cells significantly increased (P < 0.01). CONCLUSION: Cinnamaldehyde promoted the decomposition and autophagy of lipid droplets in C2C12 cells and inhibited the fusion of lipid droplets.

Effect of Peptide Drug Liraglutide Nano-Formulation Combined with Sodium-Glucose Cotransporter-2 Inhibitor on Blood Lipids in Patients with Type 2 Diabetes.

With the aging of our population and the increase in the number of obese people, diabetes has become a common disease. At present, drug treatment is mainly used for diabetes. Dyslipidemia is the main cause of diabetes. The regulation of blood lipids in diabetic patients through drugs is the key to treating diabetes. The purpose of this article is to further explore the specific effect and mechanism of peptide drug liraglutide nano-formulation combined with sodium-glucose co-transporter-2(SGCT-2) inhibitor on blood lipids in patients with type 2 diabetes. This article uses 30 people included in our hospital in 2019 2 patients with type 2 diabetes are divided into the group of peptide drug liraglutide nano preparations, the group of SGCT-2 inhibitors and the peptide drug liraglutide nano preparations combined with SGCT-2. In the inhibitor combination medication group, patients were given drug intervention according to the group name with the consent of the patients. After three days, the serum cholesterol, triglyceride, lipoprotein and lipid metabolism levels of all patients were tested. The results showed that under the intervention of peptide drug liraglutide nanoparticles combined with SGCT-2 inhibitor, the cholesterol level of patients with type 2 diabetes decreased from (368.2 ± 8.3) mmol / L to (1978.4 ± 4.7) mmol/L, triglyceride level decreased from (653.7 ± 12.5) mg/dL to (426.8 ± 9.6) mg/dl, and lipid metabolism level increased by 25.6%. Therefore, it can be seen that the peptide drug liraglutide nano preparation combined with SGCT-2 inhibitor has a certain therapeutic effect on type 2 diabetes.

Chronic exposure to environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP) disrupts lipid metabolism associated with SBP-1/SREBP and ER stress in C. elegans.

DEHP is commonly found in the environment, biota, food, and humans, raising significant health concerns. Whether developmental stage and exposure duration modify the obesogenic effects of DEHP is unclear, especially the underlying mechanisms by which chronic exposure to DEHP as well as its metabolites remain largely unknown. This study investigated the obesogenic effects of chronic DEHP exposure, with levels below environmentally-relevant amounts and provide the mechanism in Caenorhabditis elegans. We show that early-life DEHP exposure resulted in an increased lipid and triglyceride (TG) accumulation mainly attributed to DEHP itself, not its metabolite mono-2-ethylhexyl phthalate (MEHP). In addition, developmental stage and exposure timing influence DEHP-induced TG accumulation and chronic DEHP exposure resulted in the most significant effect. Analysis of fatty acid composition shows that chronic DEHP exposure altered fatty acid composition and TG, resulting in an increased ω-6/ω-3 ratio. The increased TG content by chronic DEHP exposure required lipogenic genes fat-6, fat-7, pod-2, fasn-1, and sbp-1. Moreover, chronic DEHP exposure induced XBP-1-mediated endoplasmic reticulum (ER) stress which might lead to up-regulation of sbp-1. This study suggests the possible involvement of ER stress and SBP-1/SREBP-mediated lipogenesis in chronic DEHP-induced obesogenic effects. Results from this study implies that chronic exposure to DEHP disrupts lipid metabolism, which is likely conserved across species due to evolutionary conservation of molecular mechanisms, raising concerns in ecological and human health.

Saikosaponin D attenuates metabolic associated fatty liver disease by coordinately tuning PPARα and INSIG/SREBP1c pathway.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a progressive chronic liver disease, yet there is still a lack of effective pharmacological therapies at present. Saikosaponin D (SSd) has been reported to exhibit hepatoprotective and anti-steatosis activities in our previous research. PURPOSE: The current study aims to further investigate the underlying mechanisms of SSd on MAFLD from the perspectives of the crosstalk between fatty acid (FA) biosynthesis and catabolism to provide strong support for further clinical management of MAFLD. METHODS: A MAFLD mouse model induced by a high-fat diet and glucose-fructose water (HFSW) was used for in vivo study. HepG2 cells, primary mouse hepatocytes and adipocytes were further employed for in vitro studies. RESULTS: SSd improved intracellular lipid accumulation both in the liver and adipose tissues in HFSW-fed mice. Mechanistically, SSd may serve as a potent PPARα agonist, and the activation of PPARα by SSd in both hepatocytes and adipocytes not only promoted FA oxidation but also concurrently induced INSIG1/2 expression, which subsequently inhibited SREBP1c maturation and ultimately FA synthesis. Moreover, the regulative effect of SSd on lipid metabolism was abolished by the PPARα inhibitor, GW6471. CONCLUSION: This study demonstrated that SSd improved lipid homeostasis by coordinately regulating PPARα activation-mediated both inhibition of SREBP1c-dependent FA biosynthesis and induction of FA degradation, and thus shed novel light on the discovery of SSd-based therapeutic strategies for MAFLD.

PPARα agonist WY-14,643 induces the PLA2/COX-2/ACOX1 pathway to enhance peroxisomal lipid metabolism and ameliorate alcoholic fatty liver in mice.

Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid oxidation (FAO). Usually, very-long chain fatty acids are first activated by acyl-CoA synthetase (ACS) to generate acyl-CoA for oxidation by acyl-CoA oxidase (ACOX) in peroxisomes, and the resultant shorter chain fatty acids will be further oxidized in mitochondria. ACS long-chain family member 4 (ACSL4) preferentially uses arachidonic acid (AA) as substrates to synthesize arachidonoyl-CoA. Arachidonoyl-CoA is usually esterified into phospholipids. When AA is released by phospholipase A2 (PLA2) from phospholipids, it will be used for prostaglandin synthesis by cyclooxygenases (COX). In this study, when PPARα agonist WY-14,643 was mixed in liquid Lieber-DeCarli ethanol or control diets and fed to mice, liver PLA2, COX-2, and ACOX1 were induced but ACSL4 was inhibited, suggesting that AA released by PLA2 from phospholipid will be metabolized to prostaglandin via COX-2 instead of being synthesized into acyl-CoA by ACSL4. However, liver prostaglandin E2 (PGE2), a major component of prostaglandin, was not increased with the induced COX-2 but decreased by WY-14,643. ACOX1 specific inhibitor mixed in the liquid diets restored both the WY-14,643-suppressed liver TG and PGE2, but COX-2 specific inhibitor celecoxib mixed in the liquid diets reversed the WY-14,643-suppressed liver TG but not liver PGE2 contents. These results suggest that induction of PLA2, COX-2 and ACOX1 orchestrates to increase oxidation of AA/PGE2, which constitutes one new mechanism by which PPARα induces peroxisomal FAO and inhibits ethanol-induced liver fat accumulation.

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice.

BACKGROUND: Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIM: To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODS: Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTS: The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation. CONCLUSION: PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.

The Association between Single Nucleotide Polymorphisms, including miR-499a Genetic Variants, and Dyslipidemia in Subjects Treated with Pharmacological or Phytochemical Lipid-Lowering Agents.

Disorders of lipoprotein metabolism are among the major risk factors for cardiovascular disease (CVD) development. Single nucleotide polymorphisms (SNPs) have been associated with the individual variability in blood lipid profile and response to lipid-lowering treatments. Here, we genotyped 34 selected SNPs located in coding genes related to lipid metabolism, inflammation, coagulation, and a polymorphism in the MIR499 gene-a microRNA previously linked to CVD-to evaluate the association with lipid trait in subjects with moderate dyslipidemia not on lipid-lowering treatment (Treatment-naïve (TN) cohort, n = 125) and in patients treated with statins (STAT cohort, n = 302). We also explored the association between SNPs and the effect of a novel phytochemical lipid-lowering treatment in the TN cohort. We found that 6 SNPs (in the MIR499, TNFA, CETP, SOD2, and VEGFA genes) were associated with lipid traits in the TN cohort, while no association was found with the response to twelve-week phytochemical treatment. In the STAT cohort, nine SNPs (in the MIR499, CETP, CYP2C9, IL6, ABCC2, PON1, IL10, and VEGFA genes) were associated with lipid traits, three of which were in common with the TN cohort. Interestingly, in both cohorts, the presence of the rs3746444 MIR499 SNP was associated with a more favorable blood lipid profile. Our findings could add information to better understand the individual genetic variability in maintaining a low atherogenic lipid profile and the response to different lipid-lowering therapies.