Lipogenic Genes Research Articles

Taurine Activates SIRT1/AMPK/FOXO1 Signaling Pathways to Favorably Regulate Lipid Metabolism in C57BL6 Obese Mice.

The identification of novel therapeutic agents capable of modulating lipid metabolism holds a promising potential in combating obesity and its associated complications. This study is conducted to evaluate the lipid lowering effect of dietary taurine administration on high-fat fed C57BL6 mice and to study the mechanism by which taurine impacts lipid metabolism. C57BL6 mice are grouped into four (n = 6): i) normal diet (ND), ii) a high-fat diet (HFD), iii) HFD+orlistat (STD), iv) HFD + taurine (TAU) group for 12 weeks. The results show that taurine administration for 12 weeks reduces high fat-induced weight gain, and liver weight when compared with HFD fed mice. It also improves serum biochemical parameters like total cholesterol and triglycerides. Sirtuin 1 (SIRT1) activity, Nicotinamide adenine dinucleotide (NAD+) levels, SIRT1 mRNA, and protein expression are increased in HFD+TAU diet group as compared to HFD group. Taurine treatment suppresses the expression of lipogenic genes (sterol regulatory element binding protein 1c [SREBP1c], fatty acid synthase [FAS], Peroxisome proliferator-activated receptor gamma [PPARγ]) and increases the expression of β-oxidation (peroxisome proliferator-activated receptor alpha [PPARα], liver x receptor beta [LXRβ], peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1α], AMP-activated protein kinase [AMPK]) and lipolytic (forkhead box protein O1 [FOXO1]) genes. Further, taurine mitigates hepatic inflammation by suppressing nuclear factor kappa B (NF-κB) gene expression and pro-inflammatory cytokine markers (IL-6, IL-1β, and TNFα). Taurine exerts lipid lowering effects through activating SIRT1/AMPK/FOXO1 signaling pathways and regulating their downstream targets.

Abstract 3394: Participation of molecular iodine and PPARG in prostate cancer progression and neuroendocrine differentiation

Abstract Introduction: Advanced prostate cancer (PCa) therapy is based on androgen deprivation; however, cancerous cells develop resistance, and can develop a highly aggressive neuroendocrine (NE) phenotype. Molecular iodine (I2) has antitumoral effects in breast cancer models, in which PPARG receptors represent the main mechanism of action described. In PCa though, PPARG is considered pro-tumoral and I2 effects have not been fully studied. Hence, the aim of this study was to analyze I2 individual and combined effects with androgen deprivation by using both androgen dependent (AD) and independent (AI), in vitro and in vivo PCa models. Methods: In vitro. I2 effects in cell viability and invasion were analyzed in AD (LNCaP) and AI (DU145, PC3) PCa cells. LNCaP cells were also treated with androgen receptor (AR) antagonists. PPARG participation in I2 effects was assessed with GW9962 (antagonist) and rosiglitazone (agonist). NE phenotype was induced in LNCaP by prolonged culture under androgen-depleted conditions and was assessed by measuring the growth and length of neurite-like projections. RT-qPCR was employed to assess the expression of NE markers (SYP, ENO2), and lipogenic genes (FASN, SREBF1). In vivo. Eighteen weeks-old TRAMP mice were subjected to sham surgery or castration, and were provided or not with I2 (0.025%, drinking water) for four weeks. Prostates were subjected to histopathological analysis (H&E and Masson's trichrome) and IHC (AR, SYP, PPARG). Scoring systems were used to grade the severity of high proliferative intraepithelial lesions (HPIN), and desmoplasia. Results: I2 decreased the cell viability and invasion capacity of all PCa cells tested, and when supplied with AR antagonists further enhanced their antiproliferative effects in LNCaP cells. I2 failed to induce the expression of PPARG target genes, and GW9662 did not prevent I2-induced decrease in cell viability. Like androgen deprivation, I2 also caused NE-like morphology in LNCaP cells, but unlike androgen deprived LNCaP cells, I2 treated cells had decreased expression of NE markers. In TRAMP mice, I2 increased the presence of HPIN, reduced nuclear AR protein detection, and had no effect on PPARG. As expected, castration reduced HPIN, caused epithelial atrophy and desmoplasia; decreased total AR levels and PPARG nuclear levels. However, the number of NE (SYP-positive) cells did not change. The addition of I2 to castration did not modify the score of epithelial lesions but increased the desmoplasia and the presence of NE cells. Conclusions: I2 exhibited in vitro antineoplastic effects over epithelial cells, however, these effects did not translate into the in vivo model. PPARG did not seem to mediate I2 effects. Overall, our data suggest that tumoral microenvironment may interfere with I2 epithelial-specific antitumoral effects. Funding: PAPIIT-UNAM (IN217223, IN202322) and CONAHCYT (774791). Citation Format: Carlos Montes de Oca, Lourdes Álvarez, Carmen Aceves, Brenda Anguiano. Participation of molecular iodine and PPARG in prostate cancer progression and neuroendocrine differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3394.

Abstract 4451: Regulation of lipid metabolism and ferroptosis by DAXX

Abstract Intracellular lipid production in cancer cells supplies lipids to synthesize cell membranes and signaling molecules during rapid cell proliferation and tumor growth. Cancer cells also utilize fatty acid oxidation (FAO) to generate ATP to meet their energy demand. Notably, lipid metabolites can inhibit and trigger ferroptosis due to iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). Therefore, identifying regulators that maintain the intricate balance of lipid biosynthesis required for cell proliferation and survival is critical in cancer biology and therapy. Lipid metabolism is regulated by two oncogenic signaling pathways: the RAS-RAF-MEK-MAPK and the mammalian target of rapamycin (mTOR) pathways. About 30% of all cancers harbor constitutively active mutations in KRAS, HRAS, or NRAS, resulting in hyperactive RAS-RAF-MEK-MAPK signaling to drive tumorigenesis, metastatic progression, immune evasion, and resistance to therapy. KRAS regulates lipid uptake, lipid synthesis, and FAO. mTOR is a serine/threonine kinase acting as a key intracellular signaling hub to regulate nutrient homeostasis, metabolism, protein synthesis, and autophagy. The mTORC1 complex promotes lipogenesis. The RAS and mTOR signaling pathways exhibit both positive and negative cross-regulation. The coordinated activity of both pathways is critical to sustained tumor growth. Notably, mTORC1 signaling inhibition enhances RAS-RAF-MEK-MAPK signaling to promote cancer cell survival and proliferation. Furthermore, constitutive mTORC1 signaling induces cell death when the supply of unsaturated FAs is limited. However, the molecular link for coordinating the activity of the RAS and mTOR signaling pathways remains poorly defined. Death domain-associated protein (DAXX) is essential for mouse embryonic development and has ill-defined pro-cell survival functions. Our lab has a long-standing interest in deciphering DAXX’s complex biological functions. Our recent study shows that DAXX drives tumorigenesis by promoting lipogenic gene expression and lipid synthesis through interacting with sterol regulatory element-binding proteins SREBP1 and SREBP2 (SREBP1/2) (Mahmud et al., 2023, PMID 37045819). Unexpectedly, our new data reveal that DAXX inhibits ferroptosis. Significantly, phosphorylation via RAS signaling appears to regulate DAXX’s activity in lipid synthesis and resistance to ferroptosis. Remarkably, disruption of DAXX-mediated lipid synthesis potentiates ferroptosis due to mTORC1 activity. Based on these observations, we propose that stimulated by the RAS-RAF-MEK-MAPK oncogenic signaling, DAXX promotes tumorigenesis through upregulating genes for lipid synthesis and resistance to ferroptosis, and that the lack of DAXX-mediated lipid synthesis leads to sensitization of cells to ferroptosis due to mTORC1’s proliferative effects. (Supported by FDOH grant 23K03). Citation Format: Wenlin Yang, Nikee Awasthee, Qi Chen, Seth Hale, Daiqing Liao. Regulation of lipid metabolism and ferroptosis by DAXX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4451.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

Screening of Platycodonis Radix Fractions for Antiobesity Activities and Elucidation of Its Molecular Mechanisms in High-Fat Diet-Fed C57BL/6 Mice.

Obesity is a threat to public health and effective new medications are required. Platycodonis Radix (PR) is a traditional medicinal/dietary plant with activities against obesity. Using mice given a diet rich in fat, the antiobesity components of PR were identified and their molecular mechanisms were clarified further in this investigation. Initially, the impacts of PR fractions on liver histology and biochemical markers were assessed. Subsequently, the degrees of lipogenic and lipolytic gene and protein expressions were determined. Oral administration of PR polysaccharides (PG) (0.80 g/kg body weight) improved liver function (alanine aminotransferase and aspartate aminotransferase) and its antioxidant activities (total superoxide dismutase, glutathione peroxidase, and malondialdehyde), as well as alleviated blood lipid (total cholesterol, total triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) values, inflammatory systemic (TNF-α and IL-1β), and histological abnormalities within the liver. Furthermore, PG administration downregulated the expression for lipogenic genes (ACC and FAS) and upregulated the expression for the lipolytic gene (PPARα, LPL, CPT1, and HSL). Importantly, PG raised AMPK phosphorylation and decreased SREBP-1c protein synthesis. Thus, it is possible that PG stimulates the AMPK-LPL/HSL path (lipolytic route) plus the AMPK-ACC/PPARα-CPT1 path (associated to β-oxidation of fatty acids), while inhibiting the AMPK/(SREBP-1c)-ACC/FAS path (lipogenic route). In summary, PG has the ability to regulate lipid metabolism, and it may be useful to pharmacologically activate AMPK with PG to prevent and cure obesity.

Domestication Gene Mlx and Its Partner Mondo Are Involved in Controlling the Larval Body Size and Cocoon Shell Weight of Bombyx mori.

Bombyx mori was domesticated from Bombyx mandarina. The long-term domestication of the silkworm has brought about many remarkable changes to its body size and cocoon shell weight. However, the molecular mechanism underlying the improvement in the economic characteristics of this species during domestication remains unclear. In this study, we found that a transposable element (TE)-Bm1-was present in the upstream regulatory region of the Mlx (Max-like protein X) gene in wild silkworms but not in all domesticated silkworms. The absence of Bm1 caused an increase in the promoter activity and mRNA content of Mlx. Mlx and its partner Mondo belong to the bHLHZ transcription factors family and regulate nutrient metabolism. RNAi of Mlx and Mondo decreased the expression and promoter activity of glucose metabolism-related genes (trehalose transport (Tret), phosphofructokinase (PFK), and pyruvate kinase (PK)), lipogenic genes (Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)), and glutamine synthesis gene (Glutamine synthase 2, (GS2)). Furthermore, the transgenic overexpression of Mlx and Mondo in the fat body of silkworms increased the larval body size, cocoon shell weight, and egg number, but the silencing of the two genes resulted in the opposite phenotypes. Our results reveal the molecular mechanism of Mlx selection during domestication and its successful use in the molecular breeding of Bombyx mori.

Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A.

Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, HIF1A or INSIG2 knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect.

Magnolia officinalis Rehder & E. Wilson ameliorates white adipogenesis by upregulating AMPK and SIRT1 in vitro and in vivo

Although there is an established link between Magnolia Cortex (MO) and lipid metabolism in previous research, its exploration within the context of obesity has been limited. Therefore, the present study investigated the therapeutic effects of MO on obesity and its mechanism of action in vitro and in vivo. Our chromatography analysis revealed that Honokiol and Magnolol are contained in MO extract. In vitro experiments showed that lipid droplets, adipogenic, and lipogenic genes were notably diminished by increasing sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK) protein expression in MO-treated 3T3-L1 adipocytes. In vivo experiments exhibited that MO administration significantly recovered the adipogenesis, lipogenesis, and fatty acid oxidation genes by increasing the SIRT1 and AMPK expression in white adipose tissue. Furthermore, hepatic steatosis by HFD feeding was ameliorated in MO-administered obese mice. We conclude that MO could be important manager for treating obesity through AMPK and SIRT1 regulation.

Dietary polyamines promote intestinal adaptation in an experimental model of short bowel syndrome

Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Effects of Seipin on Mouse Mesenchymal Stem Cell Osteo-Adipogenic Balance.

Seipin deficiency is an important cause of type 2 Berardinelli-Seip congenital dyslipidemia (BSCL2). BSCL2 is a severe lipodystrophy syndrome with lack of adipose tissue, hepatic steatosis, insulin resistance, and normal or higher bone mineral density. Bone marrow mesenchymal stem cells (BMSCs) are believed to maintain bone and fat homeostasis by differentiating into osteoblasts and adipocytes. We aimed to explore the role of seipin in the osteogenic/adipogenic differentiation balance of BMSCs. Seipin loxP/loxP mice are used to explore metabolic disorders caused by seipin gene mutations. Compared with wild-type mice, subcutaneous fat deficiency and ectopic fat accumulation were higher in seipin knockout mice. Microcomputed tomography of the tibia revealed the increased bone content in seipin knockout mice. We generated seipin-deficient BMSCs in vitro and revealed that lipogenic genes are downregulated and osteogenic genes are upregulated in seipin-deficient BMSCs. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) signaling is reduced in seipin-deficient BMSCs, while using the PPARγ activator increased the lipogenic differentiation and decreased osteogenic differentiation of seipin-deficient BMSCs. Our findings indicated that bone and lipid metabolism can be regulated by seipin through modulating the differentiation of mesenchymal stem cells. Thus, a new insight of seipin mutations in lipid metabolism disorders was revealed, providing a prospective strategy for MSC transplantation-based treatment of BSCL2.

Uxi (Endopleura uchi (Huber) Cuatrec) bark extract mitigates HFD-induced adiposity in rats via targeting oxidative stress, and lipogenic genes expression

Here, we compared the modulatory effects of different dose levels of Uxi (Endopleura uchi aqueous bark extract, EUAE) vs simvastatin (SIM) on hyperlipidemia, metabolic stress, and liver dysfunction in HFD-induced obese rats. HFD significantly increased BMI, lee index, body adipose index, atherogenic indices, cellular toxicity markers, blood glucose level, adipokines, pro-inflammatory mediators, lipid peroxidation and promoted lipid accumulation and HMGCR and ACC. Furthermore, it significantly decreased antioxidants, ghrelin, and AG/UAG ratio as well as hepatic glycogen content, while these changes were mitigated by either SIM or EUAE treatment. The expression of FASN & SREBP1c genes were elevated in the HFD group, with downregulation of PPARα expression. These alterations were ameliorated by SIM or EUAE treatment. The beneficial effects of EUAE may be attributed to its phenolic compounds and their derivatives. This study supports the hypothesis that Uxi may have antihyperlipidemic, antioxidant, hepatoprotective, and anti-inflammatory properties in rat model of obesity.

Elder (Sambucus nigra), identified by high-content screening, counteracts foam cell formation without promoting hepatic lipogenesis

Cholesterol deposition in intimal macrophages leads to foam cell formation and atherosclerosis. Reverse cholesterol transport (RCT), initiated by efflux of excess cholesterol from foam cells, counteracts atherosclerosis. However, targeting RCT by enhancing cholesterol efflux was so far accompanied by adverse hepatic lipogenesis. Here, we aimed to identify novel natural enhancers of macrophage cholesterol efflux suitable for the prevention of atherosclerosis. Plant extracts of an open-access library were screened for their capacity to increase cholesterol efflux in RAW264.7 macrophages trace-labeled with fluorescent BODIPY-cholesterol. Incremental functional validation of hits yielded two final extracts, elder (Sambucus nigra) and bitter orange (Citrus aurantium L.) that induced ATP binding cassette transporter A1 (ABCA1) expression and reduced cholesteryl ester accumulation in aggregated LDL-induced foam cells. Aqueous elder extracts were subsequently prepared in-house and both, flower and leaf extracts increased ABCA1 mRNA and protein expression in human THP-1 macrophages, while lipogenic gene expression in hepatocyte-derived cells was not induced. Chlorogenic acid isomers and the quercetin glycoside rutin were identified as the main polyphenols in elder extracts with putative biological action. In summary, elder flower and leaf extracts increase macrophage ABCA1 expression and reduce foam cell formation without adversely affecting hepatic lipogenesis.

Effect of Post-Weaning Concentrate Feeding Prior to Forage Finishing on Intramuscular Fat Deposition

The objectives of this study were to examine the effects of feeding high-concentrate diets post-weaning (PW) prior to forage finishing on (1) changes in ultrasound intramuscular fat deposition and lipogenic/lipolytic gene expression during the post-weaning phase and (2) carcass characteristics and fatty acid composition after forage finishing to 487 kg. Steers were randomly assigned to one of four treatments (PW0, PW40, PW80, and PW120) at weaning to examine the time of high-concentrate feeding prior to forage finishing. The ultrasound intramuscular fat content was greater (p < 0.05) for PW120 compared to those for PW0, PW40, or PW80 at the end of the post-weaning phase. Feeding high concentrates (PW120) up-regulated (p < 0.01) the mRNA expression of fatty acid transporters and lipogenic genes and down-regulated lipolytic genes in the LM compared to PW0. Carcasses from PW120 were graded 83% Choice (p = 0.025), whereas carcasses from other post-weaning treatments (PW0, 40, or 80) were graded 25, 36, and 54% Choice, respectively, at the final harvest. The total fatty acid content of the muscle at slaughter was greater (p = 0.0004) for PW120 than PW0, PW40, and PW80. Feeding high-concentrate diets to steers post-weaning for 120 day enhanced early intramuscular fat deposition without causing major changes to the fatty acid composition of the longissimus muscle after forage finishing.

Kimchi attenuates endoplasmic reticulum stress-induced hepatic steatosis in HepG2 cells and C57BL/6N mice

Kimchi is a traditional fermented food that contains abundant nutrients and functional ingredients with various health benefits. We previously reported that kimchi active components suppress hepatic steatosis caused by endoplasmic reticulum (ER) stress in vitro and in vivo. Therefore, we assessed the effect of kimchi on the inhibition of hepatic steatosis caused by ER stress in HepG2 cells and C57BL/6N mice to verify the hypothesis that kimchi may potentially inhibit nonalcoholic fatty liver disease. We investigated the effect of kimchi on cell viability and triglyceride concentrations in cells and on lipid profile, lipid accumulation, and expression of related genes in cells and mice with hepatic steatosis. A mechanistic study was also performed using the liver X receptor α agonist T0901317 and the AMP-activated protein kinase agonist AICAR. Kimchi was noncytotoxic and effectively reduced triglyceride concentrations and suppressed hepatic steatosis-related gene expression in cells and mice. Additionally, kimchi recovered weight loss, lowered the serum and liver tissue lipid profiles, suppressed lipid accumulation, and reduced the effects of T0901317 and AICAR on lipogenic gene expression in tunicamycin-treated mice. Our results highlight that kimchi could prevent hepatic steatosis caused by ER stress in cells and mice.

Excess phosphate promotes SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation via the SCAP‑SREBP2 signaling pathway.

Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can promote cardiovascular adverse events in patients with chronic kidney disease. Hyperphosphatemia is associated with elevated inflammation and sterol regulatory element binding protein 2 (SREBP2) activation, but the underlying mechanisms in SARS‑CoV‑2 that are related to cardiovascular disease remain unclear. The present study aimed to elucidate the role of excess inorganic phosphate (PI) in SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). The expression levels of SARS‑CoV‑2 N protein, SREBP cleavage‑activating protein (SCAP), mature N‑terminal SREBP2, NLRP3, procaspase‑1, cleaved caspase‑1, IL‑1β and IL‑18 were examined by western blotting. The expression levels of SREBP2, HMG‑CoA reductase, HMGCS1, low density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), SREBP1c, fatty acid synthase, stearyl coenzyme A desaturase 1, acetyl‑CoA carboxylase α and ATP‑citrate lyase were determined by reverse transcription‑quantitative PCR. The translocation of SCAP or NLRP3 from the endoplasmic reticulum to the Golgi was detected by confocal microscopy. The results showed that excess PI promoted SCAP‑SREBP and NLRP3 complex translocation to the Golgi, potentially leading to NLRP3 inflammasome activation and lipogenic gene expression. Furthermore, PI amplified SARS‑CoV‑2 N protein‑induced inflammation via the SCAP‑SREBP pathway, which facilitates NLRP3 inflammasome assembly and activation. Inhibition of phosphate uptake with phosphonoformate sodium alleviated NLRP3 inflammasome activation and reduced SREBP‑mediated lipogenic gene expression in VSMCs stimulated with PI and with SARS‑CoV‑2 N protein overexpression. Inhibition of SREBP2 or small interfering RNA‑induced silencing of SREBP2 effectively suppressed the effect of PI and SARS‑CoV‑2 N protein on NLRP3 inflammasome activation and lipogenic gene expression. In conclusion, the present study identified that PI amplified SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and lipogenic gene expression via the SCAP‑SREBP signaling pathway.

Activation of ChAT+ neuron in dorsal motor vagus (DMV) increases blood glucose through the regulation of hepatic gene expression in mice

The brain and peripheral organs communicate through hormones and neural connections. Proper communication is required to maintain normal whole-body energy homeostasis. In addition to endocrine system, from the perspective of neural connections for metabolic homeostasis, the role of the sympathetic nervous system has been extensively studied, but understanding of the parasympathetic nervous system is limited. The liver plays a central role in glucose and lipid metabolism. This study aimed to clarify the innervation of parasympathetic nervous system in the liver and its functional roles in metabolic homeostasis. The liver-specific parasympathetic nervous system innervation (PNS) was shown by tissue clearing, immunofluorescence and transgenic mice at the three-dimensional histological level. The parasympathetic efferent signals were manipulated using a chemogenetic technique and the activation of ChAT+ parasympathetic neurons in dorsal motor vagus (DMV) results in the increased blood glucose through the elevated hepatic gluconeogenic and lipogenic gene expression in the liver. Thus, our study showed the evidence of ChAT+ parasympathetic neurons in the liver and its role for hepatic parasympathetic nervous signaling in glucose homeostasis through the regulation of hepatic gene expression.

Chronic sucralose consumption inhibits farnesoid X receptor signaling and perturbs lipid and cholesterol homeostasis in the mouse livers, potentially by altering gut microbiota functions

Sucralose has raised concerns regarding its safety and recent studies have demonstrated that sucralose consumption can disrupt the normal gut microbiome and alter metabolic profiles in mice. However, the extent to which this perturbation affects the functional interaction between the microbiota and the host, as well as its potential impact on host health, remains largely unexplored. Here, we aimed to investigate whether chronic sucralose consumption, at levels within the Acceptable Daily Intake (ADI), could disturb key gut microbial functions and lead to adverse health effects in mice. Following six-month sucralose consumption, several bacterial genera associated with bile acid metabolism were decreased, including Lactobacillus and Ruminococcus. Consequently, the richness of secondary bile acid biosynthetic pathway and bacterial bile salt hydrolase gene were decreased in the sucralose-treated gut microbiome. Compared to controls, sucralose-consuming mice exhibited significantly lower ratios of free bile acids and taurine-conjugated bile acids in their livers. Additionally, several farnesoid X receptor (FXR) agonists were decreased in sucralose-treated mice. This reduction in hepatic FXR activation was associated with altered expression of down-stream genes, in the liver. Moreover, the expression of key lipogenic genes was up-regulated in the livers of sucralose-treated mice. Changes in hepatic lipid profiles were also observed, characterized by lower ceramide levels, a decreased PC/PE ratio, and a mildly increase in lipid accumulation. Additionally, sucralose-consumed mice exhibited higher hepatic cholesterol level compared to control mice, with up-regulation of cholesterol efflux genes and down-regulation of genes associated with reverse cholesterol transport. In conclusion, chronic sucralose consumption disrupts FXR signaling activation and perturbs hepatic lipid and cholesterol homeostasis, potentially by diminishing the bile acid metabolic capacity of the gut microbiome. These findings shed light on the complex interplay between sucralose, the gut microbiota, and host metabolism, raising important questions about the safety of its long-term consumption.

Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.

The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).

Effects of dietary Clostridium butyricum and rumen protected fat on meat quality, oxidative stability, and chemical composition of finishing goats

BackgroundClostridium butyricum (CB) is a probiotic that can regulate intestinal microbial composition and improve meat quality. Rumen protected fat (RPF) has been shown to increase the dietary energy density and provide essential fatty acids. However, it is still unknown whether dietary supplementation with CB and RPF exerts beneficial effects on growth performance and nutritional value of goat meat. This study aimed to investigate the effects of dietary CB and RPF supplementation on growth performance, meat quality, oxidative stability, and meat nutritional value of finishing goats. Thirty-two goats (initial body weight, 20.5 ± 0.82 kg) were used in a completely randomized block design with a 2 RPF supplementation (0 vs. 30 g/d) × 2 CB supplementation (0 vs. 1.0 g/d) factorial treatment arrangement. The experiment included a 14-d adaptation and 70-d data and sample collection period. The goats were fed a diet consisted of 400 g/kg peanut seedling and 600 g/kg corn-based concentrate (dry matter basis).ResultInteraction between CB and RPF was rarely observed on the variables measured, except that shear force was reduced (P < 0.05) by adding CB or RPF alone or their combination; the increased intramuscular fat (IMF) content with adding RPF was more pronounced (P < 0.05) with CB than without CB addition. The pH24h (P = 0.009), a* values (P = 0.007), total antioxidant capacity (P = 0.050), glutathione peroxidase activities (P = 0.006), concentrations of 18:3 (P < 0.001), 20:5 (P = 0.003) and total polyunsaturated fatty acids (P = 0.048) were increased, whereas the L* values (P < 0.001), shear force (P = 0.050) and malondialdehyde content (P = 0.044) were decreased by adding CB. Furthermore, CB supplementation increased essential amino acid (P = 0.027), flavor amino acid (P = 0.010) and total amino acid contents (P = 0.024) as well as upregulated the expression of lipoprotein lipase (P = 0.034) and peroxisome proliferator-activated receptor γ (PPARγ) (P = 0.012), and downregulated the expression of stearoyl-CoA desaturase (SCD) (P = 0.034). The RPF supplementation increased dry matter intake (P = 0.005), averaged daily gain (trend, P = 0.058), hot carcass weight (P = 0.046), backfat thickness (P = 0.006), concentrations of 16:0 (P < 0.001) and c9-18:1 (P = 0.002), and decreased the shear force (P < 0.001), isoleucine (P = 0.049) and lysine content (P = 0.003) of meat. In addition, the expressions of acetyl-CoA carboxylase (P = 0.003), fatty acid synthase (P = 0.038), SCD (P < 0.001) and PPARγ (P = 0.022) were upregulated due to RPF supplementation, resulting in higher (P < 0.001) content of IMF.ConclusionsCB and RPF could be fed to goats for improving the growth performance, carcass traits and meat quality, and promote fat deposition by upregulating the expression of lipogenic genes of Longissimus thoracis muscle.

Optimization of soybean oil content in a soybean oil-based aquafeed for grass carp (Ctenopharyngodon idella) to achieve optimal growth performance, proximate and fatty acid compositions, and lipid metabolism

Soybean oil (SO), an important plant-derived lipid, is routinely used in aquafeed as a partial substitute for fish oil. However, the effect of various contents of SO in a SO-based aquafeed on specific aquatic animals and the underlying mechanisms are unclear. In this study, five isonitrogenous diets containing different SO contents (0 %, 3 %, 6 %, 9 %, and 12 %, named as S0, S3, S6, S9, and S12, respectively) were prepared with SO as the predominant lipid source, and 12-week feeding experiments were conducted on juvenile grass carp (Ctenopharyngodon idella) (initial weight: 12.54 ± 0.08 g). Apart from lower feed conversion ratio in the S6 and S9 groups (P < 0.05), no obvious changes were observed in other growth indices (e.g., final weight and weight gain rate) in grass carp fed on diets with 0–9 % SO (P > 0.05). The S12 group exhibited significant decrease in the final weight and weight gain rate and increase in the viscerosomatic index (P < 0.05). Unlike gradual decrease in moisture, ash, and saturated fatty acid contents, muscle crude fat and unsaturated fatty acid (particularly polyunsaturated fatty acid) contents significantly increased with the increasing SO contents (P < 0.05). Serum triglyceride contents continuously increased with the increasing SO amounts, exhibiting the maximum value in the S12 group (P < 0.05). Similarly, the S12 group displayed the highest levels of aspartate aminotransferase, alanine transaminase, low-density lipoprotein cholesterol, and total cholesterol in serum (P < 0.05). Only the S12 group exhibited scanty lymphocytic infiltration in some areas of the hepatopancreas. However, other groups exhibited no obvious histopathological abnormalities. Lipogenic genes (dgat, fad, elovl1, elovl6, elovl7, lpcat, and pla2), ACSL family members (acsl1a, acsl1b, acsl3, acsl4, acsl5, and acsl6), lipolytic genes (atg1, cpt1a, cpt1b, hsl, and lpl), fatty acid transport-related genes (cd36, fabp, and fatp), and transcription factor involved in lipid metabolism (ppar α) were gradually upregulated as dietary SO content increased (P < 0.05). However, the transcript levels of srebp1 and its target gene acc1 exhibited decreasing trend under the same conditions, and significant downregulation of ppar γ was observed in the S12 group (P < 0.05). In conclusion, the optimal content of SO as the main lipid source in a SO-based diet for juvenile grass carp ranged from 6 % to 9 %, at which growth requirements of grass carp were met and fish health and fillet quality were effectively maintained. Our data provided a scientific reference for developing more efficient aquafeed formulations and enhancing fish flesh quality in aquaculture, as well as provided basic information for further assessing the regulatory mechanism of lipid homeostasis in teleost fishes.