Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

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.

Tanshinone IIA reverses gefitinib resistance in EGFR-mutant lung cancer via inhibition of SREBP1-mediated lipogenesis.

BACKGROUND AND AIM: Gefitinib resistance is an urgent problem to be solved in the treatment of non-small cell lung cancer (NSCLC). Tanshinone IIA (Tan IIA) is one of the main active components of Salvia miltiorrhiza, which exhibits significant antitumor effects. The aim of this study is to explore the reversal effect of Tan IIA on gefitinib resistance in the epidermal growth factor receptor (EGFR)-mutant NSCLC and the underlying mechanism. EXPERIMENTAL PROCEDURE: CCK-8, colony formation assay, and flow cytometry were applied to detect the cytotoxicity, proliferation, and apoptosis, respectively. The changes in lipid profiles were measured by electrospray ionization-mass spectrometry (MS)/MS. Western blot, real-time q-PCR, and immunohistochemical were used to detect the protein and the corresponding mRNA levels. The in vivo antitumor effect was validated by the xenograft mouse model. KEY RESULTS: Co-treatment of Tan IIA enhanced the sensitivity of resistant NSCLC cells to gefitinib. Mechanistically, Tan IIA could downregulate the expression of sterol regulatory element binding protein 1 (SREBP1) and its downstream target genes, causing changes in lipid profiles, thereby reversing the gefitinib-resistance in EGFR-mutant NSCLC cells in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: Tan IIA improved gefitinib sensitivity via SREBP1-mediated lipogenesis. Tan IIA could be a potential candidate to enhance sensitivity for gefitinib-resistant NSCLC patients.

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.

Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.

Effects of essential oil mixtures on expression of genes involved in lipogenesis and fatty acid oxidation in geese (Anser anser).

The use of essential oils has recently increased in the poultry sector. The aim of this study was to investigate the effects of essential oil mixture (juniper, mint, oregano and rosemary oil) on fatty acid oxidation and lipogenic gene expression in geese. Research groups were formed as C (control; no additives), EK1 (0.4 ml/l essential oil mixture supplemented) and EK2 (0.8 ml/l essential oil mixture supplemented). Relative expression levels of genes included in lipogenesis (ACCα, ChREBP, FASN, LXRα and SREBP-1) expression levels of genes included in fatty acid oxidation (ACOX1, CPT1, CPT1A, PPARα and PPARγ) were measured using RT-qPCR. Group EK1 upregulates the mRNA expression levels of genes involved in lipogenesis such as ACCα, ChREBP and SREBP-1, while it downregulates the mRNA expression in levels of all genes involved in fatty acid oxidation. Group EK2 increases the mRNA expression levels of genes involved in lipogenesis such as ACCα, FASN and SREBP-1, while it decreased mRNA expression at the levels of all genes involved in fatty acid oxidation, as in the other group. In the study, adding an essential oil mixture to drinking water is predicted to increase fatty liver because it upregulates genes related to fat synthesis (lipogenesis) and downregulates genes related to fat degradation (fatty acid oxidation).

Stearic acid promotes lipid synthesis through CD36/Fyn/FAK/mTORC1 axis in bovine mammary epithelial cells.

Stearic acid (C18:0, SA) is a saturated long-chain fatty acid (LCFA) that has a prominent function in lactating dairy cows. It is obtained primarily from the diet and is stored in the form of triacylglycerol (TAG) molecules. The transmembrane glycoprotein cluster of differentiation 36 (CD36) is also known as fatty acid translocase, but whether SA promotes lipid synthesis through CD36 and FAK/mTORC1 signaling is unknown. In this study, we examined the function and mechanism of CD36-mediated SA-induced lipid synthesis in bovine mammary epithelial cells (BMECs). SA-enriched supplements enhanced lipid synthesis and the FAK/mTORC1 pathway in BMECs. SA-induced lipid synthesis, FAK/mTORC1 signaling, and the expression of lipogenic genes were impaired by anti-CD36 and the CD36-specific inhibitor SSO, whereas overexpression of CD36 effected the opposite results. Inhibition of FAK/mTORC1 by TAE226/Rapamycin attenuated SA-induced TAG synthesis, inactivated FAK/mTORC1 signaling, and downregulated the lipogenic genes PPARG, CD36, ACSL1, SCD, GPAT4, LIPIN1, and DGAT1 at the mRNA and protein levels in BMECs. By coimmunoprecipitation and yeast two-hybrid screen, CD36 interacted directly with Fyn but not Lyn, and Fyn bound directly to FAK; FAK also interacted directly with TSC2. CD36 linked FAK through Fyn, and FAK coupled mTORC1 through TSC2 to form the CD36/Fyn/FAK/mTORC1 signaling axis. Thus, stearic acid promotes lipogenesis through CD36 and Fyn/FAK/mTORC1 signaling in BMECs. Our findings provide novel insights into the underlying molecular mechanisms by which LCFA supplements promote lipid synthesis in BMECs.

Lipid Disorders and Metabolic-Associated Fatty Liver Disease.

Dyslipidemia has been linked metabolic-associated fatty liver disease (MAFLD). Several genes and transcription factors involved in lipid metabolism can increase susceptibility to MAFLD. Multiple parallel 'hits' have been proposed for developing hepatic steatosis, NASH, and MAFLD, including insulin resistance and subsequent free fatty acid excess, de novo lipogenesis, and excessive hepatic triglyceride and cholesterol deposition in the liver. This lead to defective beta-oxidation in the mitochondria and VLDL export and increased inflammation. Given the significant cardiovascular risk, dyslipidemia associated with MAFLD should be managed by lifestyle changes and lipid-lowering agents such as statins, fenofibrate, and omega-3 fatty acids, with judicious use of insulin-sensitizing agents, and adequate control of dysglycemia.

Dipterocarpus tuberculatus as a promising anti-obesity treatment in Lep knockout mice.

Introduction: The therapeutic effects and mechanisms of Dipterocarpus tuberculatus (D. tuberculatus) extracts have been examined concerning inflammation, photoaging, and gastritis; however, their effect on obesity is still being investigated. Methods: We administered a methanol extract of D. tuberculatus (MED) orally to Lep knockout (KO) mice for 4 weeks to investigate the therapeutic effects on obesity, weight gain, fat accumulation, lipid metabolism, inflammatory response, and ß-oxidation. Results: In Lep KO mice, MED significantly reduced weight gains, food intake, and total cholesterol and glyceride levels. Similar reductions in fat weights and adipocyte sizes were also observed. Furthermore, MED treatment reduced liver weight, lipid droplet numbers, the expressions of adipogenesis and lipogenesis-related genes, and the expressions of lipolysis regulators in liver tissues. Moreover, the iNOS-mediated COX-2 induction pathway, the inflammasome pathway, and inflammatory cytokine levels were reduced, but ß-oxidation was increased, in the livers of MED-treated Lep KO mice. Conclusion: The results of this study suggest that MED ameliorates obesity and has considerable potential as an anti-obesity treatment.

Wen-Shen-Jian-Pi-Hua-Tan decoction protects against early obesity-related glomerulopathy by improving renal bile acid composition and suppressing lipogenesis, inflammation, and fibrosis.

BACKGROUND: Obesity is an independent predictor of chronic kidney disease (CKD) development and may directly lead to kidney lesions such as obesity-related glomerulopathy (ORG) which might play a vital pathogenic role in obese patients with CKD. Wen-Shen-Jian-Pi-Hua-Tan decoction (WSHT) has been clinically used for the treatment of obesity and obesity-related metabolic diseases for years. However, the renoprotective effects and potential mechanism of action of WSHT against ORG remain unknown. PURPOSE: This study aimed to explore the potential effect of WSHT on ORG and reveal its mechanisms in high-fat diet (HFD)-induced obese rats. METHODS: An animal model of early stage ORG was established using HFD-induced obese rats. After treatment with WSHT for 6 weeks, an integrated metabolomics and molecular biology strategy was utilized to illustrate the effects and mechanism of WSHT on ORG. First, UPLC-ESI-MS/MS-based targeted metabolomics was used to analyze renal bile acid (BA) levels. Biochemical, histological, and immunofluorescence assays; electron microscopy; and western blotting were performed to evaluate the efficacy of WSHT against ORG and its underlying mechanisms in vivo. RESULTS: Our results showed that an HFD led to hyperlipidemia, proteinuria, renal lipid deposition, effacement of podocyte foot processes, and increased expression of proinflammatory factors and profibrotic growth factors in ORG rats. In addition, an HFD decreased the levels of renal BAs such as cholic acid, chenodeoxycholic acid, and lithocholic acid. After 6 weeks of treatment, WSHT markedly attenuated dyslipidemia and reduced body, kidney and epididymal fat weights in ORG rats. WSHT also significantly increased BA levels, suggesting that it altered BA composition; the effects of BAs are closely associated with farnesoid X receptor (FXR) activation. WSHT alleviated fat accumulation, podocyte loss and proteinuria, and reduced the expression of proinflammatory cytokines and profibrotic growth factors in the kidneys of ORG rats. Finally, WSHT remarkably upregulated the renal expression of FXR and salt-induced kinase 1 and blocked the renal expression of sterol regulatory element-binding protein-1c and its target genes. CONCLUSION: WSHT attenuated early renal lesions in ORG rats by improving renal BA composition and suppressing lipogenesis, inflammation and fibrosis. This study develops a new way to alleviate obesity-induced renal damages.

Effect of dietary inclusion of atorvastatin, garlic, and dill on growth performance, antioxidant defense, gut, and cardio-pulmonary function, and lipogenesis in broiler chickens.

In the present study, we evaluated the antihyperlipidemic and antioxidant effects of garlic and dill in comparison with atorvastatin to combat lipogenesis in broiler chickens. A total of 400 1-day-old chicks (Ross 308 strain) were randomly distributed into four experimental diets. Dietary treatments included a control diet, the control diet plus atorvastatin at 20 mg/kg, the control diet plus garlic dry powder (GDP) at 7.5 g/kg, and the control diet plus dill dry powder (DDP) at 7.5 g/kg. Chicks were maintained on experimental diets for 42 days under the recommended environmental conditions set out by the strain management manual. The results showed that weight gain, feed conversion ratio (FCR), and duodenal, jejunal, and ileal dimensions of villi (height, width, and the surface absorptive area) were improved by in-feed atorvastatin, GDP, or DDP when compared to the control (P < 0.05). The inclusion of atorvastatin or phytobiotic products increased circulatory levels of nitric oxide (NO) but decreased circulatory levels of malondialdehyde (MDA), triacylglycerol (TAG), and low-density lipoproteins cholesterol (LDL), with concomitant reductions in the T, R, and S waves amplitudes in the Lead 2 electrocardiogram (ECG) (P < 0.05). Dietary supplements caused an up-regulation of inducible nitric oxide synthase (iNOS), superoxide dismutase 1 (SOD1), and glutathione peroxidase (GPX) but reduced the expression of key hepatic lipogenic enzymes (fatty acid synthase (FAS) and hydroxy-methylglutaryl-CoA reductase (HMGCR) (P < 0.05). In conclusion, feed supplementation with atorvastatin, GDP, or DDP suppressed lipogenesis, enhanced antioxidant response, and improved gut and cardio-pulmonary function in broiler chicks subjected to hypobaric hypoxia.

γ-Linolenic Acid-Rich Oil- and Fish Oil-Induced Alterations of Hepatic Lipogenesis, Fatty Acid Oxidation, and Adipose Tissue mRNA Expression in Obese KK-A y Mice.

The physiological activity of γ-linolenic acid (GLA)-rich evening primrose oil and eicosapentaenoic and doxosahexaenoic acids-rich fish oil, which affect hepatic fatty acid oxidation and synthesis, and adipose tissue mRNA expression were compared in diabetic obese KK-A y mice. The mice were fed diets containing 100 g/kg of either palm oil (saturated fat), GLA oil, or fish oil for 21 days. These oils, compared with palm oil, greatly increased the activity and mRNA levels of hepatic fatty acid oxidation enzymes. These oils also increased the carnitine concentrations and mRNA levels of carnitine transporter (solute carrier family 22, member 5) in the liver. In general, these effects were comparable between GLA and fish oils. In contrast, GLA and fish oils, compared with palm oil, reduced the activity and mRNA levels of the proteins related to hepatic lipogenesis, except for those of malic enzyme. The reducing effect was stronger for fish oil than for GLA oil. These changes were accompanied by reductions in the triacylglycerol levels in the serum and liver. The reduction in the liver was stronger for fish oil than for GLA oil. These oils also reduced epididymal adipose tissue weight accompanied by a reduction in the mRNA levels of several proteins that regulate adipocyte functions; these effects were stronger for fish oil than for GLA oil. These oils were also effective in reducing serum glucose levels. Therefore, both fish oil and GLA-rich oil were effective at ameliorating metabolic disorders related to obesity and diabetes mellitus.

Ameliorative effect of sesame oil on experimentally induced polycystic ovary syndrome: A cross-link between XBP-1/PPAR-1, regulatory proteins for lipogenesis/steroids.

Polycystic ovary syndrome (PCOS) is a mixed endocrine/metabolic/reproductive disorder in women of reproductive age. Sesame oil (SO) contains sesame lignans & vitamin E with broad-spectrum antioxidant and anti-inflammatory effects. This study investigates the ameliorative effect of SO on experimentally induced PCOS and elucidates the possible molecular mechanisms with a deeper focus on the different signaling pathways involved. The study was carried out on 28 nonpregnant female Wister albino rats that were divided into four equal groups; Group I (control group) received oral 0.5% wt/vol carboxymethyl cellulose daily. Group II (SO group): orally administered SO (2 mL/kg body wt./day) for 21 days. Group III (PCOS group) received letrozole daily, 1 mg/kg, for 21 days. Group IV (PCOS + SO group): concomitantly administered letrozole and SO for 21 days. The serum hormonal and metabolic panel and the homogenate ATF-1, StAR, MAPK, PKA, and PI3K levels of the ovarian tissue were calorimetrically evaluated. However, endoplasmic reticulum (ER) stress was evaluated by ovarian XBP1 and PPAR-γ messenger RNA expression level using the qRT-PCR technique. Ovarian COX-2 was detected immunohistochemically. The results suggest that SO-treated PCOS rats showed a significantly improved hormonal, metabolic panel, inflammatory, and ER stress status with concomitant decreases in ATF-1, StAR, MAPK, PKA, and PI3K in ovarian rats compared to the correspondent values in PCOS without treatment. CONCLUSIONS: The protective effects of SO against PCOS are triggered by ameliorating regulatory proteins of ER stress, lipogenesis, and steroidogenesis through the PI3K/PKA and MAPK/ERK2 signaling cascades. SIGNIFICANCE STATEMENT: Polycystic ovary syndrome (PCOS) is the most common mixed endocrine-metabolic dysfunction among women within the reproductive period, with an estimated prevalence of 5%-26% worldwide. Doctors traditionally recommend metformin for PCOS patients. However, metformin is known to be associated with significant adverse effects and contraindications. This work aimed at shedding light on the ameliorative effect of sesame oil (SO), natural polyunsaturated fatty acids-rich oil, on the induced PCOS model. SO proved to have a marvelous effect on the metabolic and endocrine derangements in the PCOS rat model. We hoped to provide a valuable alternative treatment for PCOS patients to avoid the side effects of metformin and to help PCOS patients for whom metformin is contraindicated.

Molecular mechanism of valine and its metabolite in improving triglyceride synthesis of porcine intestinal epithelial cells.

An insufficient energy supply to intestinal epithelial cells decreases production performance in weaned piglets. Triglycerides are the main energy source for intestinal epithelial cells in piglets. The present study aimed to investigate the effects and mechanisms of valine supplementation on triglyceride synthesis in porcine intestinal epithelial (IPEC-J2) cells. Valine supplementation in the medium significantly increased the content of triglycerides, fat droplets, and long-chain fatty acids (C17:0, C18:0, C20:0, C18:1, C20:1, and C22:1) (P < 0.05). Valine metabolite (3-hydroxyisobutyrate [3-HIB]) concentration increased significantly in the valine-supplemented group (P < 0.05). Silencing of the 3-HIB synthase enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in IPEC-J2 cells significantly reduced the triglyceride concentration and lipid droplet synthesis. Further studies found that 3-HIB supplementation in the medium significantly increased the concentration of triglycerides, lipid droplets, and unsaturated fatty acids (C16:1, C18:1, C18:2, C18:3, C20:3, C20:4, and C20:5) (P < 0.05) by upregulating the expression of proteins involved in fatty acid transport (CD36) and fatty acid binding protein 3 (FABP3) or triglyceride synthesis (DGAT1) (P < 0.05), indicating that 3-HIB mediates valine-enhanced triglyceride synthesis in IPEC-J2 cells. In conclusion, our results demonstrated that valine enhanced triglyceride synthesis in IPEC-J2 cells via increasing the 3-HIB concentration, which may promote fatty acid transport via upregulation of proteins related to fatty acid transporter. These findings provide new insights into the mechanisms through which valine participates in lipid metabolism.

Standardized Ethanol Extract of Cassia mimosoides var. nomame Makino Ameliorates Obesity via Regulation of Adipogenesis and Lipogenesis in 3T3-L1 Cells and High-Fat Diet-Induced Obese Mice.

Obesity is a major cause of conditions such as type 2 diabetes and non-alcoholic fatty liver disease, posing a threat to public health worldwide. Here, we analyzed the anti-obesity effects of a standardized ethanol extract of Cassia mimosoides var. nomame Makino (EECM) in vitro and in vivo. Treatment of 3T3-L1 adipocytes with EECM suppressed adipogenesis and lipogenesis via the AMP-activated protein kinase pathway by downregulating the expression levels of CCAAT/enhancer-binding protein-alpha, peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1, and fatty acid synthase and upregulating the acetyl-CoA carboxylase. EECM inhibited mitotic clonal expansion during early adipocyte differentiation. Oral administration of EECM for 10 weeks significantly alleviated body weight gain and body fat accumulation in high-fat diet (HFD)-fed mice. EECM mitigated adipogenesis and lipid accumulation in white adipose and liver tissues of HFD-induced obese mice. It regulated the levels of adipogenic hormones including insulin, leptin, and adipokine in the blood plasma. In brown adipose tissue, EECM induced the expression of thermogenic factors such as uncoupling protein-1, PPAR-α, PPARγ co-activator-1α, sirtuin 1, and cytochrome c oxidase IV. EECM restored the gut microbiome composition at the phylum level and alleviated dysbiosis. Therefore, EECM may be used as a promising therapeutic agent for the prevention of obesity.

Branched-chain amino acids alter cellular redox to induce lipid oxidation and reduce de novo lipogenesis in the liver.

Metabolic and molecular interactions between branched-chain amino acid (BCAA) and lipid metabolism are evident in insulin-resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1.5X BCAAs (LB), high-fat (HF) or HF diet plus 1.5X BCAAs (HB) for 12 wk. Hepatic metabolism was profiled utilizing stable isotopes coupled to mass spectrometry and nuclear magnetic resonance, together with fed-to-fasted changes in gene and protein expression. A greater induction of lipid oxidation and ketogenesis on fasting was evident in the BCAA-supplemented, insulin-sensitive livers from LB mice, whereas their rates of hepatic de novo lipogenesis remained lower than their LF counterparts. Onset of insulin resistance in HF and HB mice livers blunted these responses. Whole body turnover of BCAAs and their ketoacids, their serum concentrations, and the ketogenic flux from BCAA catabolism, all remained similar between fasted LF and LB mice. This suggested that the impact of BCAAs on lipid metabolism can occur independent of them or their degradation products fueling anaplerosis through the liver mitochondria. Furthermore, the greater induction of lipid oxidation in the LB livers accompanied higher mitochondrial NADH/NAD+ ratio and higher fed-to-fasting phosphorylation of AMPKα and ACC. Taken together, our results provide evidence that BCAA supplementation, under conditions of insulin sensitivity, improved the feeding-to-fasting induction of hepatic lipid oxidation through changes in cellular redox, thus providing a favorable biochemical environment for flux through ß-oxidation and lower de novo lipogenesis.NEW & NOTEWORTHY Branched-chain amino acids (BCAAs) have been shown to modulate lipid metabolic networks in various tissues, especially during insulin resistance. In this study we show that the dietary supplementation of BCAAs to normal, insulin-sensitive mice resulted in higher mitochondrial NADH:NAD+ ratios and AMPK activation in the liver. This change in the cellular redox status provided an optimal metabolic milieu to increase fatty acid oxidation while keeping the rates of de novo lipogenesis lower in the BCAA-supplemented mice livers.

Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation.

The coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2), has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2-/-) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage, including the liver, brain, and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain, and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate that Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions and acts as a transcriptional regulatory enzyme.

Bufalin Inhibits Tumorigenesis and SREBP-1-Mediated Lipogenesis in Hepatocellular Carcinoma via Modulating the ATP1A1/CA2 Axis.

Altered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.

Gallic acid impairs fructose-driven de novo lipogenesis and ameliorates hepatic steatosis via AMPK-dependent suppression of SREBP-1/ACC/FASN cascade.

Accumulating evidence suggests that de novo lipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis, oxidative stress, and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice and in vitro. Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/ß subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesis via AMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis.

Inhibition on XBP1s-driven lipogenesis by Qushi Huayu Decoction contributes to amelioration of hepatic steatosis induced by fructose.

ETHNOPHARMACOLOGICAL RELEVANCE: Qushi Huayu Decoction (QHD) is a traditional Chinese medicine formula consisting of five herbs, which has been used for non-alcoholic fatty liver disease (NAFLD) treatment in clinic for decades in China and validated in several NAFLD animal models. The hepatic de novo lipogenesis (DNL) is enhanced greatly to contribute to steatosis in NAFLD. The spliced form of X-box binding protein 1 (XBP1s) initiates DNL independently of sterol regulatory element-binding protein (SREBP) and carbohydrate-responsive element-binding protein (ChREBP). AIM OF THE STUDY: To disclose the mechanism of inhibition on hepatic DNL by QHD and the responsible compounds. METHODS: The effects of QHD on hepatic DNL were evaluated in mice induced by high-fructose diet (HFru). The effects of the serum-absorbed compounds of QHD on XBP1s were evaluated in HepG2 cells induced by tunicamycin. Hepatic histology, triglyceride (TG) and nonesterified fatty acids were observed. Hepatic apolipoprotein B100 and very low-density lipoprotein were measured to reflect lipid out-transport. The mRNA expression of XBP1s and its target genes were detected by real-time polymerase chain reaction. The protein expression of TG synthetases and DNL enzymes, and inositol requirement enzyme 1 alpha (IRE1α), phosphorylated IRE1α and XBP1s were detected in liver tissue and HepG2 cells by western-blot. The binding activity of SREBP1, protein expression of ChREBP and XBP1s were detected in the nuclear extracts of liver tissue. RESULTS: Dynamical observing suggested feeding with HFru for 2 weeks was sufficient to induce hepatic lipogenesis and XBP1s. QHD ameliorated liver steatosis without enhancing out-transport of lipids, accompanied with more inhibitory effects on DNL enzymes than TG synthetases. QHD inhibits the nuclear XBP1s without affecting ChREBP and SREBP1. In QHD, chlorogenic acid, geniposide and polydatin inhibit lipogenesis initiated by XPB1s. CONCLUSION: QHD probably decreases hepatic DNL by inhibiting XBP1s independent of SREBP1 and ChREBP. Chlorogenic acid, geniposide and polydatin are the potential responsible compounds.

Inhibition of lipogenesis and sebum secretion for Lotus corniculatus seed extract in vitro and in vivo.

BACKGROUND: Botanical ingredients are widely used in hair- and skin-care products. However, few studies have investigated the effectiveness of botanical products on counteracting sebum synthesis and secretion. OBJECTIVE: To investigate the composition of Lotus corniculatus seed extract (LC) and its potential inhibition of lipogenesis in SZ95 sebocytes and oily human skin. METHODS: The active components of LC solutions were identified by high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR). The in vitro effects of LC were evaluated using SZ95 cells treated with linoleic acid (LA) and dihydrotestosterone (DHT) and incubated with LCs for 24 h and 72 h. Lipogenesis was assessed by Oil Red O and Nile Red staining of the cells. In vivo effects were assessed on 30 subjects with oily skin who were enrolled in a randomized, blank-controlled trial and were treated with LC solution for 6 h and 4 weeks. The skin sebum contents and area on the forehead and cheeks were evaluated using a Sebumeter SM815 and Sebfix sebutape with Visioscan VC98. In addition, VISIA was used to collect half-face photos for analysis. RESULTS: A novel active molecule, 5'-o-rhamnosyl uridine, was identified in LC. LC exhibited a dose-dependent inhibitory effect on LA and DHT-induced lipid synthesis. When 5% LC was applied for 3 h, the skin sebum contents and area were significantly reduced compared with the vehicle control, with an obvious reduction after 6 h. Continued use of the serum containing 5% LC for 4 weeks resulted in a significant reduction in the skin sebum contents and area. No adverse reactions were reported during the study. CONCLUSIONS: Topical application of LC resulted in an immediate and long-lasting reduction of the sebum contents and area of oily human skin by reducing sebaceous lipogenesis through the LA and DHT pathways. This indicates the potential of LC as a new biological treatment for oily skin.

CONTEXTE: Les ingrédients végétaux sont largement utilisés dans les produits de soins des cheveux et de la peau. Cependant, peu d'études ont examiné l'efficacité des produits végétaux dans l'inhibition de la synthèse et de la sécrétion de sébum. OBJECTIF: Étudier les composants de l'extrait de graines de lotus (LC) et son effet inhibiteur potentiel sur la lipogenèse des cellules sébacées SZ95 et de la peau grasse. MÉTHODES: Les composants actifs de la solution LC ont été identifiés par chromatographie liquide à haute performance (HPLC) et par résonance magnétique nucléaire (NMR). Les effets de la LC in vitro ont été évalués à l'aide de cellules SZ95 traitées à l'acide linoléique (LA) et à la dihydrotestostérone (DHT) et incubées avec la LC pendant 24 et 72 heures. Les effets in vivo ont été évalués chez 30 sujets à peau grasse qui ont participé à un essai contrôlé randomisé à blanc et qui ont été traités avec une solution de LC pendant 6 heures et 4 semaines. Le sebumeter SM815 et le sebfix sebutape et le visioscan VC98 ont été utilisés pour évaluer la teneur en sébum et la surface de la peau sur le front et les joues. De plus, des photos de demi - visage ont été recueillies pour analyse à l'aide de VISIA. RÉSULTATS: Une nouvelle molécule active, 5'-o-rhamnosyluridine, a été identifiée dans la LC. La LC a un effet inhibiteur dose - dépendant sur la synthèse lipidique induite par LA et DHT. La teneur et la surface du sébum cutané ont été significativement diminuées par rapport à celles du support photographique après 3 heures d'application de 5% de LC, et significativement diminuées après 6 heures. L'utilization de sérum contenant 5% de LC pendant quatre semaines consécutives a entraîné une réduction significative de la teneur en sébum et de la surface de la peau. Aucun effet indésirable n'a été signalé au cours de l'étude. CONCLUSION: L'application topique de LC peut réduire la production de sébum par les voies LA et DHT, ce qui réduit immédiatement et durablement la teneur en sébum et la surface de la peau huileuse humaine. Cela démontre le potentiel de la LC en tant que nouveau traitement biologique de la peau huileuse.