FABP1 induces lipogenesis by regulating the processing of SREBP1 in hepatocytes of large yellow croaker (Larimichthys crocea).

Fatty acid-binding protein 1 (FABP1) plays an important role in regulating fatty acid metabolism in liver, which is a potential therapeutic target for diseases such as non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered FABP1 induction in hepatocytes as a primary mediator of lipogenesis when exposed to fatty acids, especially saturated fatty acids (SFAs). In the feeding trial, palm oil led to excess lipid accumulation in the liver of large yellow croaker (Larimichthys crocea), accompanied by significant induction of FABP1. In cultured cells, palmitic acid (PA), a kind of SFA, triggered the fabp1 expression and increased triglyceride (TG) contents. Knockdown of FABP1 dampened PA-induced TG accumulation through mitigated lipogenesis. The overexpression of FABP1 showed the opposite result. Furthermore, the inactivation of FABP1 led to induction in insulin-induced gene 1 (INSIG1) expression, which attenuated the processing of sterol regulatory element-binding protein 1 (SREBP1) by down-regulating the nuclear-localized SREBP1. These results revealed a previously unrecognized function of FABP1 in response to PA, providing additional evidence for targeting FABP1 in the treatment of NAFLD caused by SFA.

Hexavalent chromium reduces testosterone levels by impairing lipophagy and disrupting lipid metabolism homeostasis: Based on a metabolomic analysis.

Hexavalent chromium (Cr(VI)) causes testicular damage and reduces testosterone secretion. Testosterone synthesis relies on cholesterol as a raw material, and its availability can be affected by lipophagy. However, the role of lipophagy in Cr(VI)-induced testicular damage and reduced testosterone secretion remains unclear. In this study, we investigated the effect of Cr(VI) on lipid metabolism and lipophagy in the testes of ICR mice. Forty mice were randomly divided into four groups and exposed to different doses of Cr(VI) (0, 75, 100, 125 mg/kg) for thirty days. Cr(VI) increased the rate of sperm abnormalities, decreased testosterone level, and decreased the levels of testosterone synthesis-related proteins, namely steroidogenic acute regulatory (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) proteins. Through metabolomic analysis, Oil Red O staining, and biochemical indicator (triglyceride and total cholesterol) analysis, Cr(VI) was found to disrupt testicular lipid metabolism. Further investigation revealed that Cr(VI) inhibited the AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein 1 (SREBP1) pathway, elevated levels of the autophagy-related proteins microtubule-associated protein 1 light chain 3B (LC3B) and sequestosome 1 (SQSTM1)/P62 and lipophagy-related proteins Rab7 and Rab10, while increasing colocalization of LC3B and Perilipin2. These findings suggest that Cr(VI) exposure leads to abnormal lipid metabolism in the testes by suppressing the AMPK/SREBP1 pathway and disrupting lipophagy, ultimately reducing testosterone level and inducing testicular damage.

Exploring the effect and mechanism of Hippophae rhamnoides L. triterpenoid acids on improving NAFLD based on network pharmacology and experimental validation in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides L.) is a traditional Chinese medicinal and possesses a rich medical history in terms of treating gastric disorders, sputum and cough and liver injuries in oriental medicinal system. By reason of the complicated chemical constituents, the material basis and potential pharmacological mechanism of sea buckthorn acting on Non-alcoholic fatty liver disease (NAFLD) has not been clearly elucidated. AIM OF THE STUDY: To explore the pharmacological efficacy and underlying mechanism of sea buckthorn triterpenoid acid enrichment (STE) in the treatment of NAFLD. MATERIALS AND METHODS: The approaches of Network pharmacology and experiment validation in vitro and in vivo were applied in this study. Firstly, targets of triterpenoid acid compounds and NAFLD were collected from databases. The crucial targets were screened by the construction of protein-protein interaction (PPI) network. Furthermore, the potential signaling pathways and targets affected by STE was predicted by GO together with KEGG enrichment analysis. Finally, the experiment validation was carried out through high-fat feeding NAFLD mice and lipid accumulation HepG2 cell model. Lipids and liver related biochemical indicators were determined, Oil Red O and H&E staining were employed to observe fat accumulation. In addition, the expression levels of proteins of key target and signal pathway anticipated in network pharmacology were detected to elaborated its action mechanism. RESULTS: A total of 180 intersecting potential targets for enhancing NAFLD with STE were eventually identified. 6 key targets including AKT1, TNF, IL6, INS, JUN, STAT3 and TP53 were further identified and the AMPK-SREBP1 pathway was enriched. Animal experiment result showed that STE treatment could significantly reduce the levels of TG, TC, LDL-C, ALT and AST, increase the levels of HDL-C in serum, and improve lipid accumulation of epididymal fat and liver. The results of the lipid accumulation cell model indicated that STE and key compound oleanolic acid could diminish intracellular lipid levels of TG, TC, LDL-C and number of lipid droplets. Western blot results showed that the above beneficial effects could be achieved by regulating the expression of p-AMPK/AMPK, SREBP1, FAS, ACC, SCD protein. CONCLUSION: This study confirmed the effect of STE on improving NAFLD and the potential action mechanism was involved in the regulation of the AMPK-SREBP1 pathway.

Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to release their transcription-activating domains, which enhance the synthesis of fatty acids, triglycerides, and cholesterol. Heretofore, the two Insigs have redundant functions, and there is no rationale for two isoforms. The current data identify a specific function for Insig-2. We show that eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, inhibits fatty acid synthesis in human fibroblasts and rat hepatocytes by activating adenylate cyclase, which induces protein kinase A (PKA) to phosphorylate serine-106 in Insig-2. Phosphorylated Insig-2 inhibits the proteolytic processing of SREBP-1, thereby blocking fatty acid synthesis. Phosphorylated Insig-2 does not block the processing of SREBP-2, which activates cholesterol synthesis. Insig-1 lacks serine-106 and is not phosphorylated at this site. EPA inhibition of SREBP-1 processing was reduced by the replacement of serine-106 in Insig-2 with alanine or by treatment with KT5720, a PKA inhibitor. Inhibition did not occur in mutant human fibroblasts that possess Insig-1 but lack Insig-2. These data provide an Insig-2-specific mechanism for the long-known inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Fatty acid synthesis is indispensable for Kupffer cells to eliminate bacteria in ALD progression.

BACKGROUND: Dysregulated fatty acid metabolism is closely linked to the development of alcohol-associated liver disease (ALD). KCs, which are resident macrophages in the liver, play a critical role in ALD pathogenesis. However, the effect of alcohol on fatty acid metabolism in KCs remains poorly understood. The current study aims to investigate fatty acid metabolism in KCs and its potential effect on ALD development. METHODS: Wild-type C57BL/6 mice were fed a Lieber-DeCarli ethanol liquid diet for 3 days. Then, the liver injury and levels of intrahepatic bacteria were assessed. Next, we investigated the effects and underlying mechanisms of ethanol exposure on fatty acid metabolism and the phagocytosis of KCs, both in vivo and in vitro. Finally, we generated KCs-specific Fasn knockout and overexpression mice to evaluate the impact of FASN on the phagocytosis of KCs and ethanol-induced liver injury. RESULTS: Using Bodipy493/503 to stain intracellular neutral lipids, we found significantly reduced lipid levels in KCs from mice fed an alcohol-containing diet for 3 days and in RAW264.7 macrophages exposed to ethanol. Mechanistically, alcohol exposure suppressed sterol regulatory element-binding protein 1 transcriptional activity, thereby inhibiting fatty acid synthase (FASN)-mediated de novo lipogenesis in macrophages both in vitro and in vivo. We show that genetic ablation and pharmacologic inhibition of FASN significantly impaired KC's ability to take up and eliminate bacteria. Conversely, KCs-specific Fasn overexpression reverses the impairment of macrophage phagocytosis caused by alcohol exposure. We also revealed that KCs-specific Fasn knockout augmented KCs apoptosis and exacerbated liver injury in mice fed an alcohol-containing diet for 3 days. CONCLUSIONS: Our findings indicate the crucial role of de novo lipogenesis in maintaining effective KCs phagocytosis and suggest a therapeutic target for ALD based on fatty acid synthesis in KCs.

FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice. METHODS: KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected. RESULTS: Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue. CONCLUSION: Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.

CLDN6 inhibits breast cancer growth and metastasis through SREBP1-mediated RAS palmitoylation.

BACKGROUND: Breast cancer (BC) ranks as the third most fatal malignant tumor worldwide, with a strong reliance on fatty acid metabolism. CLDN6, a candidate BC suppressor gene, was previously identified as a regulator of fatty acid biosynthesis; however, the underlying mechanism remains elusive. In this research, we aim to clarify the specific mechanism through which CLDN6 modulates fatty acid anabolism and its impact on BC growth and metastasis. METHODS: Cell function assays, tumor xenograft mouse models, and lung metastasis mouse models were conducted to evaluate BC growth and metastasis. Human palmitic acid assay, triglyceride assay, Nile red staining, and oil red O staining were employed to investigate fatty acid anabolism. Reverse transcription polymerase chain reaction (RT-PCR), western blot, immunohistochemistry (IHC) assay, nuclear fractionation, immunofluorescence (IF), immunoprecipitation and acyl-biotin exchange (IP-ABE), chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP) were applied to elucidate the underlying molecular mechanism. Moreover, tissue microarrays of BC were analyzed to explore the clinical implications. RESULTS: We identified that CLDN6 inhibited BC growth and metastasis by impeding RAS palmitoylation both in vitro and in vivo. We proposed a unique theory suggesting that CLDN6 suppressed RAS palmitoylation through SREBP1-modulated de novo palmitic acid synthesis. Mechanistically, CLDN6 interacted with MAGI2 to prevent KLF5 from entering the nucleus, thereby restraining SREBF1 transcription. The downregulation of SREBP1 reduced de novo palmitic acid synthesis, hindering RAS palmitoylation and subsequent endosomal sorting complex required for transport (ESCRT)-mediated plasma membrane localization required for RAS oncogenic activation. Besides, targeting inhibition of RAS palmitoylation synergized with CLDN6 to repress BC progression. CONCLUSIONS: Our findings provide compelling evidence that CLDN6 suppresses the palmitic acid-induced RAS palmitoylation through the MAGI2/KLF5/SREBP1 axis, thereby impeding BC malignant progression. These results propose a new insight that monitoring CLDN6 expression alongside targeting inhibition of palmitic acid-mediated palmitoylation could be a viable strategy for treating oncogenic RAS-driven BC.

Lycium chinense Mill Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo.

This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes.

Upregulation of fatty acid synthesis genes in the livers of adolescent female rats caused by inhalation exposure to PCB52 (2,2',5,5'-Tetrachlorobiphenyl).

Elevated airborne PCB levels in older schools are concerning due to their health impacts, including cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular issues, neurodevelopmental diseases, and diabetes. During a four-week inhalation exposure to PCB52, an air pollutant commonly found in school environments, adolescent rats exhibited notable presence of PCB52 and its hydroxylated forms in their livers, alongside changes in gene expression. Female rats exhibited more pronounced changes in gene expression compared to males, particularly in fatty acid synthesis genes regulated by the transcription factor SREBP1. In vitro studies with human liver cells showed that the hydroxylated metabolite of PCB52, 4-OH-PCB52, but not the parent compound, upregulated genes involved in fatty acid biosynthesis similar to in vivo exposure. These findings highlight the sex-specific effects of PCB52 exposure on livers, particularly in females, suggesting a potential pathway for increased MASLD susceptibility.

Hypericum perforatum-derived exosomes-like nanovesicles for adipose tissue photodynamic therapy.

BACKGROUND: Recent investigations underscore the capacity of photodynamic therapy (PDT) to induce adipocyte apoptosis, thereby mitigating obesity. Nonetheless, extant synthetic photosensitizers manifest limitations that hinder their clinical viability. PURPOSE: In the current study, we used Hypericum perforatum-derived exosomes-like nanovesicles (HPExos) as a novel photosensitizer, and investigated its PDT effects in adipose tissue during obesity. METHOD: HPExos-were administered to high fat diet mice via intraperitoneal injection, followed by targeted irradiation with specialized LED lights. Mass spectrometric analysis was analyzed in adipose tissues. CCK8 assay and Oil Red O staining were used to investigate lipid accumulation in 3T3-L1 cells to clarify adipocyte differentiation. The expression levels of related markers associated with adipogenesis and lipogenesis were assessed by RT-PCR. Apoptosis analysis was performed by TUNEL staining of and western blotting. RESULTS: HPExos combined with PDT accumulated in visceral white adipose tissues results in a reduced body weight and improved insulin sensitivity. HPExos combined with PDT induced apoptosis by driving high levels of ROS. In addition, HPExos combined with PDT significantly downregulated the expression of transcription factors, PPARγ, C/EBPα, and SREBP and lipogenesis protein FABP4 both in vitro and in vivo, associated with a decreased FFA levels. CONCLUSION: These findings suggest that HPExos could act as an effective photosensitizer in regulating glucose hemostasis by inhibiting adipocyte differentiation and lipogenesis, offering a promising approach for obesity treatment.

BI-7273, a BRD9 inhibitor, reduces lipid accumulation by downregulating the AKT/mTOR/SREBP1 signaling pathway.

Increases in de novo lipogenesis that disturbed lipid homeostasis and caused lipid accumulation are a major cause of NAFLD and obesity. SREBP1 is a crucial regulatory factor controlling the expression of rate-limiting enzymes of lipid synthesis. A reduction in SREBP1expression can reduce lipid accumulation. Thus, we utilized an SREBP1-luciferase-KI HEK293 cell line constructed by our lab to screen 200 kinds of epigenetic drugs for their ability to downregulate SREBP1expression. BI-7273, an inhibitor of bromodomain-containing protein 9 (BRD9), was screened and found to decrease SREBP1 expression. What is more, BI-7273 has been confirmed that it could reduce lipid accumulation in HepG2 cells by BODIPY staining, and significantly decrease the protein expression of SREBP1 and FASN. To explore the potential mechanism BI-7273 reducing lipid accumulation, RNA sequencing (RNA-seq) was performed and demonstrated that BI-7273 reduced lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vitro. Finally, these results were verified in NAFLD and obesity mouse model induced by high fat diet (HFD). The results indicated that BI-7273 could decrease mouse body weight and improve insulin sensitivity, but also exhibited a strong negative correlation with serum lipid levels, and also demonstrated that BI-7273 reduced lipid accumulation via AKT/mTOR/SREBP1 pathway in vivo. In conclusion, our results revealed that BI-7273 decreases lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vivo and in vitro. This is the first report demonstrating the protective effect of this BRD9 inhibitor against NAFLD and obesity. BRD9 may be a novel target for the discovery of effective drugs to treat lipid metabolism disorders.

Nutriomic Effects of Precision Lipids on Murine Hepatic Triacylglycerol Alterations Induced by High-Fat Diets.

INTRODUCTION: This study aims to investigate if a mixture of functional lipids (FLs), containing conjugated linoleic acid (CLA), tocopherols (TPs), and phytosterols (PSs), prevents some lipid alterations induced by high-fat (HF) diets, without adverse effects. METHODS: Male CF1 mice (n = 6/group) were fed (4 weeks) with control (C), HF, or HF + FL diets. RESULTS: FL prevented the overweight induced by the HF diet and reduced the adipose tissue (AT) weight, associated with lower energy efficiency. After the intervention period, the serum triacylglycerol (TAG) levels in both HF diets underwent a decrease associated with an enhanced LPL activity (mainly in muscle). The beneficial effect of the FL mixture on body weight gain and AT weight might be attributed to the decreased lipogenesis, denoted by the lower mRNA levels of SREBP1-c and ACC in AT, as well as by an exacerbated lipid catabolism, reflected by increased mRNA levels of PPARα, ATGL, HSL, and UCP2 in AT. Liver TAG levels were reduced in the HF + FL group due to an elevated lipid oxidation associated with a higher CPT-1 activity and mRNA levels of PPARα and CPT-1a. Moreover, genes linked to fatty acid biosynthesis (SREBP1-c and ACC) showed decreased mRNA levels in both HF diets, this finding being more pronounced in the HF + FL group. CONCLUSION: The administration of an FL mixture (CLA + TP + PS) prevented some lipid alterations induced by a HF diet, avoiding frequent deleterious effects of CLA in mice through the modulation of gene expression related to the regulation of lipid metabolism.

Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.

Salusin­α alleviates lipid metabolism disorders via regulation of the downstream lipogenesis genes through the LKB1/AMPK pathway.

Lipid metabolism disorders are a major cause of several chronic metabolic diseases which seriously affect public health. Salusin­α, a vasoactive peptide, has been shown to attenuate lipid metabolism disorders, although its mechanism of action has not been reported. To investigate the effects and potential mechanisms of Salusin­α on lipid metabolism, Salusin­α was overexpressed or knocked down using lentiviral vectors. Hepatocyte steatosis was induced by free fatty acid (FFA) after lentiviral transfection into HepG2 cells. The degree of lipid accumulation was assessed using Oil Red O staining and by measuring several biochemical indices. Subsequently, bioinformatics was used to analyze the signaling pathways that may have been involved in lipid metabolism disorders. Finally, semi­quantitative PCR and western blotting were used to verify the involvement of the liver kinase B1 (LKB1)/AMPK pathway. Compound C, an inhibitor of AMPK, was used to confirm this mechanism's involvement further. The results showed that Salusin­α significantly attenuated lipid accumulation, inflammation and oxidative stress. In addition, Salusin­α increased the levels of LKB1 and AMPK, which inhibited the expression of sterol regulatory element binding protein­1c, fatty acid synthase and acetyl­CoA carboxylase. The addition of Compound C abrogated the Salusin­α­mediated regulation of AMPK on downstream signaling molecules. In summary, overexpression of Salusin­α activated the LKB1/AMPK pathway, which in turn inhibited lipid accumulation in HepG2 cells. This provides insights into the potential mechanism underlying the mechanism by which Salusin­α ameliorates lipid metabolism disorders while identifying a potential therapeutic target.

SREBP-1-mediated lipogenesis confers resistance to ferroptosis and improves endothelial injury.

Atherosclerosis refers to a disease characterized by the formation of lipid plaque deposits within arterial walls, leading to reduced blood flow or blockage of blood outflow. The process of endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) is considered the initial stage of atherosclerosis. Ferroptosis is a form of iron-dependent, non-apoptotic cell death, and current research suggests its association with coronary artery disease (CAD). In this study, we observed a correlation between reduced expression of SREBP-1 and the occurrence of stable CAD. Additionally, during the process of endothelial injury induced by ox-LDL, we also noted decreased expression of the SREBP-1/SCD1/FADS2 and involvement in the ferroptosis process. Mechanistically, ox-LDL induced endothelial injury by inhibiting the lipid biosynthesis process mediated by the SREBP-1/SCD1/FADS2, thereby inducing lipid peroxidation and ferroptosis. On the contrary, overexpression of SREBP-1 or supplementation with monounsaturated fatty acids counteracted iron accumulation, mitochondrial damage, and lipid peroxidation-induced ferroptosis, thereby improving endothelial injury. Our study indicated that the decreased expression of peripheral blood SREBP-1 mRNA is an independent risk factor for stable CAD. Furthermore, in endothelial cells, the lipid biosynthesis process mediated by SREBP-1 could ameliorate endothelial injury by resisting ferroptosis. The study has been registered with the Chinese Clinical Trial Registry, which serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform (ChiCTR2300074315, August 3rd, 2023).

Genetic Markers Related to Meat Quality Properties in Fattened HF and HF x Charolaise Steers.

This study involved 45 Holstein and 60 Holstein-Charolaise steers, tailored with specific diets according to breed and rearing systems. DNA genotyping was conducted for DGAT1, LEP, SCD1, SREBF1, and TG genes to investigate their impact on carcass conformation traits, beef quality traits, and sensory quality traits. The results showed associations between the genetic variants and the analyzed traits. Specifically, DGAT1 was found to affect drip loss, meat brightness, and color saturation. The TG gene was associated with marbling and meat color. LEP influenced trim fat and pH levels, while SCD1 was linked to metabolic energy live weight gains, and pH levels. SREBF1 was related to fatness.

Patchouli alcohol alleviates metabolic dysfunction-associated steatohepatitis via inhibiting mitochondria-associated endoplasmic reticulum membrane disruption-induced hepatic steatosis and inflammation in rats.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by abnormal hepatic steatosis and inflammation. Previous studies have shown that Patchouli alcohol (PA), the primary component of Pogostemonis Herba, can alleviate digestive system diseases. However, its protection against MASH remains unclear. This study explored the protective effects and underlying mechanism of PA against high-fat diet-induced MASH in rats. Results showed that PA considerably reduced body weight, epididymal fat, and liver index and attenuated liver histological injury in MASH rats. PA alleviated hepatic injury by inhibiting steatosis and inflammation. These effects are associated with the improvement of SREBP-1c- and PPARα-mediated lipid metabolism and inhibition of the STING-signaling pathway-mediated inflammatory response. Moreover, PA-inhibited hepatic endoplasmic reticulum (ER) stress and mitochondrial dysfunction, reducing SREBP-1c and STING expressions and enhance PPARα expression. PA treatment had the strongest effect on the regulation of mitogen fusion protein 2 (Mfn2) in inhibiting mitochondrial dysfunction. Mfn2 is an important structural protein for binding ERs and mitochondria to form mitochondria-associated ER membranes (MAMs). MASH-mediated disruption of MAMs was inhibited after PA treatment-induced Mfn2 activation. Therefore, the pharmacological effect of PA on MASH is mainly attributed to the inhibition of MAM disruption-induced hepatic steatosis and inflammation. The findings of this study may have implications for MASH treatment that do not neglect the role of Mfn2-mediated MAMs.

Bta-miR-200a Regulates Milk Fat Biosynthesis by Targeting IRS2 to Inhibit the PI3K/Akt Signal Pathway in Bovine Mammary Epithelial Cells.

Milk fat synthesis has garnered significant attention due to its influence on the quality of milk. Recently, an increasing amount of proofs have elucidated that microRNAs (miRNAs) are important post-transcriptional factor involved in regulating gene expression and play a significant role in milk fat synthesis. MiR-200a was differentially expressed in the mammary gland tissue of dairy cows during different lactation periods, which indicated that miR-200a was a candidate miRNA involved in regulating milk fat synthesis. In our research, we investigated the potential function of miR-200a in regulating milk fat biosynthesis in bovine mammary epithelial cells (BMECs). We discovered that miR-200a inhibited cellular triacylglycerol (TAG) synthesis and suppressed lipid droplet formation; at the same time, miR-200a overexpression suppressed the mRNA and protein expression of milk fat metabolism-related genes, such as fatty acid synthase (FASN), peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), CCAAT enhancer binding protein alpha (CEBPα), etc. However, knocking down miR-200a displayed the opposite results. We uncovered that insulin receptor substrate 2 (IRS2) was a candidate target gene of miR-200a through the bioinformatics online program TargetScan. Subsequently, it was confirmed that miR-200a directly targeted the 3'-untranslated region (3'-UTR) of IRS2 via real-time fluorescence quantitative PCR (RT-qPCR), western blot analysis, and dual-luciferase reporter gene assay. Additionally, IRS2 knockdown in BMECs has similar effects to miR-200a overexpression. Our research set up the mechanism by which miR-200a interacted with IRS2 and discovered that miR-200a targeted IRS2 and modulated the activity of the PI3K/Akt signaling pathway, thereby taking part in regulating milk fat synthesis in BMECs. Our research results provided valuable information on the molecular mechanisms for enhancing milk quality from the view of miRNA-mRNA regulatory networks.

Postbiotics Prepared Using Lactobacillus reuteri Ameliorates Ethanol-Induced Liver Injury by Regulating the FXR/SHP/SREBP-1c Axis.

SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.

Chlormequat chloride induces hepatic steatosis by promoting mTOR/SREBP1 mediated lipogenesis via AMPK inhibition.

Chlormequat chloride (CCC), a widely used plant growth regulator, is a choline analogue that has been shown to have endocrine-disrupting effects. Previous studies have shown that maternal exposure to CCC could induce hyperlipidemia and growth disruption in rat offspring. This study aims to further investigate the effects of peripubertal exposure to CCC on pubertal development and lipid homeostasis, as well as the underlying mechanisms. In vivo, male weanling rats were exposed to CCC (0, 20, 75 and 200 mg/kg bw/day) from post-natal day 21-60 via daily oral gavage. The results in rats showed that 75 mg/kg CCC treatment induced hepatic steatosis, predominantly microvesicular steatosis with a small amount of macrovesicular steatosis, in rat livers and 200 mg/kg CCC treatment induced liver damage including inflammatory infiltration, hepatic sinusoidal dilation and necrosis. In vitro, HepG2 cells were treated with CCC (0, 30, 60, 120, 240 and 480 µg/mL) for 24 h. And the results showed that CCC above 120 µg/mL induced an increase in triglyceride and neutral lipid levels of HepG2 cells. Mechanism exploration revealed that CCC treatment promoted the activation of mTOR/SREBP1 signalling pathway and inhibited activation of AMPK in both in vivo rat livers and in vitro HepG2 cells. Treatment with AMPK activator Acadesine (AICAR) could alleviate the lipid accumulation in HepG2 cells induced by CCC. Collectively, the present results indicate that CCC might induce hepatic steatosis by promoting mTOR/SREBP1 mediated lipogenesis via AMPK inhibition.