Metabolic diseases characterized by an imbalance in energy homeostasis represent a significant global health challenge. Individuals with metabolic diseases often suffer from complications related to disorders in lipid metabolism, such as obesity and non-alcoholic fatty liver disease (NAFLD). Understanding core genes involved in lipid metabolism can advance strategies for the prevention and treatment of these conditions. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in lipid metabolism that converts saturated fatty acids into monounsaturated fatty acids. SCD1 plays a crucial regulatory role in numerous physiological and pathological processes, including energy homeostasis, glycolipid metabolism, autophagy, and inflammation. Abnormal transcription and epigenetic activation of Scd1 contribute to abnormal lipid accumulation by regulating multiple signaling axes, thereby promoting the development of obesity, NAFLD, diabetes, and cancer. This review comprehensively summarizes the key role of SCD1 as a metabolic hub gene in various (patho)physiological contexts. Further it explores potential translational avenues, focusing on the development of novel SCD1 inhibitors across interdisciplinary fields, aiming to provide new insights and approaches for targeting SCD1 in the prevention and treatment of metabolic diseases.
Stearoyl-CoA Desaturase/metabolism* ; Humans ; Metabolic Diseases/physiopathology* ; Lipid Metabolism/physiology* ; Animals ; Obesity/enzymology* ; Non-alcoholic Fatty Liver Disease

Cancer stem cells (CSCs) are widely acknowledged as primary mediators to the initiation and progression of tumors. The association between microbial infection and cancer stemness has garnered considerable scholarly interest in recent years. Porphyromonas gingivalis (P. gingivalis) is increasingly considered to be closely related to the development of oral squamous cell carcinoma (OSCC). Nevertheless, the role of P. gingivalis in the stemness of OSCC cells remains uncertain. Herein, we showed that P. gingivalis was positively correlated with CSC markers expression in human OSCC specimens, promoted the stemness and tumorigenicity of OSCC cells, and enhanced tumor formation in nude mice. Mechanistically, P. gingivalis increased lipid synthesis in OSCC cells by upregulating the expression of stearoyl-CoA desaturase 1 (SCD1) expression, a key enzyme involved in lipid metabolism, which ultimately resulted in enhanced acquisition of stemness. Moreover, SCD1 suppression attenuated P. gingivalis-induced stemness of OSCC cells, including CSCs markers expression, sphere formation ability, chemoresistance, and tumor growth, in OSCC cells both in vitro and in vivo. Additionally, upregulation of SCD1 in P. gingivalis-infected OSCC cells was associated with the expression of KLF5, and that was modulated by P. gingivalis-activated NOD1 signaling. Taken together, these findings highlight the importance of SCD1-dependent lipid synthesis in P. gingivalis-induced stemness acquisition in OSCC cells, suggest that the NOD1/KLF5 axis may play a key role in regulating SCD1 expression and provide a molecular basis for targeting SCD1 as a new option for attenuating OSCC cells stemness.
Porphyromonas gingivalis/pathogenicity* ; Stearoyl-CoA Desaturase/metabolism* ; Humans ; Carcinoma, Squamous Cell/pathology* ; Mouth Neoplasms/metabolism* ; Animals ; Neoplastic Stem Cells/microbiology* ; Mice, Nude ; Mice ; Nod1 Signaling Adaptor Protein/metabolism* ; Kruppel-Like Transcription Factors/metabolism* ; Cell Line, Tumor

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains (stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.
Animals ; Ceramides ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Epidermis ; Fatty Acids, Nonesterified ; Humans ; Hyperglycemia ; Kidney ; Liver ; Mice ; Receptors, Cytoplasmic and Nuclear ; Skin ; Stearoyl-CoA Desaturase ; Subcutaneous Fat

BACKGROUND/AIMS: Hepatic steatosis is caused by an imbalance between free fatty acids (FFAs) uptake, utilization, storage, and disposal. Understanding the molecular mechanisms involved in FFAs accumulation and its modulation could drive the development of potential therapies for Nonalcoholic fatty liver disease. The aim of the current study was to explore the effects of picroside II, a phytoactive found in Picrorhiza kurroa, on fatty acid accumulation vis-à-vis silibinin, a known hepatoprotective phytoactive from Silybum marianum. METHODS: HepG2 cells were loaded with FFAs (oleic acid:palmitic acid/2:1) for 20 hours to mimic hepatic steatosis. The FFAs concentration achieving maximum fat accumulation and minimal cytotoxicity (500 μM) was standardized. HepG2 cells were exposed to the standardized FFAs concentration with and without picroside II pretreatment. RESULTS: Picroside II pretreatment inhibited FFAs-induced lipid accumulation by attenuating the expression of fatty acid transport protein 5, sterol regulatory element binding protein 1 and stearoyl CoA desaturase. Preatreatment with picroside II was also found to decrease the expression of forkhead box protein O1 and phosphoenolpyruvate carboxykinase. CONCLUSIONS: These findings suggest that picroside II effectively attenuated fatty acid accumulation by decreasing FFAs uptake and lipogenesis. Picroside II also decreased the expression of gluconeogenic genes.
Fatty Acid Transport Proteins ; Fatty Acids, Nonesterified ; Hep G2 Cells* ; Lipogenesis ; Milk Thistle ; Non-alcoholic Fatty Liver Disease ; Phosphoenolpyruvate ; Picrorhiza ; Stearoyl-CoA Desaturase ; Sterol Regulatory Element Binding Protein 1

Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC50 value of 36.2 μM, compared with EC50 values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis.
Esters ; Lipid Metabolism ; Parasites ; Stearoyl-CoA Desaturase ; Toxoplasma* ; Toxoplasmosis ; Vero Cells

BACKGROUND: Excess body fat accumulation contributes to the development of metabolic disorders that can cause adverse health effects. Carnosic acid (CA), a major bioactive component of rosemary (Rosemarinus officinalis), has been suggested to possess anti-adipogenic properties. The present study was conducted to elucidate the mechanism underlying the anti-adipogenic effects of CA. METHODS: 3T3-L1 pre-adipocytes were treated with CA (0.1, 1, and 10 muM) from day 0 to day 8 of differentiation. On day 8, biochemical markers of lipid accumulation and the degree of fatty acid desaturation were measured. RESULTS: Oil Red O staining results, triglyceride (TG) accumulation, and glycerol 3-phosphate dehydrogenase activity suggested that CA significantly inhibited lipid accumulation in 3T3-L1 adipocytes. CA significantly decreased mRNA expression of peroxisome proliferator-activated receptor-gamma, sterol regulatory element-binding protein 1, and CCAAT/enhancer binding protein-alpha in a dose-dependent manner. Moreover, it decreased the ratio of both C16:1/C16:0 and C18:1/C18:0, with reduced expression of stearoyl CoA desaturase 1 mRNA and protein. CONCLUSIONS: These results suggest that CA efficiently suppressed adipogenesis in 3T3-L1 adipocytes and its action, at least in part, is associated with the downregulation of adipogenesis-related genes and the fatty acid composition of TG accumulated in adipocytes.
Adipocytes* ; Adipogenesis ; Adipose Tissue ; Biomarkers ; Down-Regulation ; Glycerol ; Oxidoreductases ; Peroxisomes ; RNA, Messenger ; Stearoyl-CoA Desaturase ; Sterol Regulatory Element Binding Protein 1 ; Triglycerides

PURPOSE: Stearoyl-CoA desaturase 1 (SCD1) is a novel therapeutic target in various malignancies, including breast cancer. The present study was designed to investigate the effect of the pharmacologic inhibition of SCD1 on fatty acid composition in tissue explant cultures of human breast cancer and to compare these effects with those in adjacent nonneoplastic breast tissue. METHODS: Paired samples of tumor and adjacent noncancerous tissue were isolated from 12 patients with infiltrating ductal breast cancer. Samples were explant cultured in vitro, exposed to the highly selective SCD1 inhibitor CAY10566, and examined for fatty acid composition by gas liquid chromatography. The cytotoxic and antigrowth effects were evaluated by quantification of lactate dehydrogenase release and by sulforhodamine B (SRB) measurement, respectively. RESULTS: Breast cancer tissue samples were found to have higher levels of monounsaturated fatty acids (MUFA) (p<0.001) and arachidonic acid (20:4n-6, p<0.001) and a lower level of linoleic acid (18:2n-6, p=0.02) than the normal-appearing breast tissues. While exhibiting no evident cytotoxicity, treatment with the SCD1 inhibitor, CAY10566 (0.1-1 microM), for 48 hours significantly increased 18:2n-6 levels in both the tumor and adjacent normal-appearing tissue (approximately 1.2 fold, p<0.05). However, the breast cancer tissue samples showed significant increases in the levels of MUFA and 20:4n-6 compared to the normal-appearing breast tissues (p<0.05). The SRB growth assay revealed a higher rate of inhibition with the SCD1 inhibitor in breast cancer tissues than in normal-appearing tissues (p<0.01, 41% vs. 29%). The SCD1 inhibitor also elevated saturated fatty acid (1.46-fold, p=0.001) levels only in the tumor tissue explant. CONCLUSION: The fatty acid composition and response to SCD1 inhibition differed between the explant cultures from breast cancer and the adjacent normal-appearing tissue. Altered fatty acid composition induced by SCD1 inhibition may also, in addition to Delta9 desaturation, modulate other reactions in de novo fatty acid synthesis and lipogenesis, and subsequently affect the overall survival and progression of breast cancer.
Arachidonic Acid ; Breast ; Breast Neoplasms* ; Chromatography, Liquid ; Fatty Acid Desaturases ; Fatty Acids, Monounsaturated ; Humans ; L-Lactate Dehydrogenase ; Linoleic Acid ; Lipogenesis ; Stearoyl-CoA Desaturase* ; Tissue Culture Techniques

OBJECTIVETo investigate the protective mechanism of stearoyl-CoA desaturase 1 (SCD1) over-expression against the pro-apoptotic affects of palmitic acid on hepatocytes using the rat BRL cell line.

METHODSConcentration effect curves were generated using the trypan blue exclusion test to assess the death rate of BRL cells upon exposure to a dilution series of palmitic acid. The multiplicity of infection (MOI) of a lentiviral expression vector, pGC-FU-GFP, was determined for the BRL cells. Unmanipulated BRL cells were divided into two groups: the non-palmitate groups were composed of ordinary cultured cells (CON) alone, infected with lentivirus empty expression vector (negative control, NC), and infected with lentivirus overexpressing SCD1 (SCD1-LV); the palmitate groups were composed of ordinary cultured cells plus palmitate (CON+) alone, infected with lentivirus empty expression vector plus palmitate (NC+), and infected with lentivirus overexpressing SCD1 plus palmitate (SCD1-LV+). SCD1 mRNA expression was detected by real-time PCR. Propidium iodide (PI) single-staining was used to detect apoptosis and assess the cell cycle. Inter-group differences were analyzed statistically.

RESULTSThe death rate of BRL cells increased significantly after 72 h of exposure to 400 mumol/L palmitate (P less than 0.01). The MOI of pGC-FU-GFP in BRL cells was 20. The expression of SCD1 was significantly higher in the SCD1-LV and SCD1-LV+ groups than in the respective controls (vs. CON: F = 289, P less than 0.01; vs. CON+: F = 1522, P less than 0.01). Palmitate exposure led to decreased expression of SCD1 (CON+ vs. CON, F = 22, P less than 0.05 and NC+ vs. NC: F = 34, P less than 0.05). The ratio of S stage cells was similar in all non-palmitate groups (CON, NC and SCD1-LV, P = 0.137). However, there was a significant apoptotic peak and lower ratio of S stage cells in the control palmitate groups (CON+ and NC+) and the activity of cell proliferation was decreased as well. The ratio of apoptotic cells was decreased significantly in the SCD1-LV+ group compared to the CON+ group (P less than 0.01).

CONCLUSIONThe expression of SCD1 and its desaturation activity increased in BRL cells upon infection with the pGC-FU-SCD1-GFP lentiviral vector, suggesting that SCD1 over-expression can decrease palmitic acid-induced toxicity and apoptosis in hepatocytes.

Animals ; Apoptosis ; Cell Line ; Genetic Vectors ; Hepatocytes ; metabolism ; Lentivirus ; genetics ; Palmitic Acid ; toxicity ; Rats ; Stearoyl-CoA Desaturase ; metabolism

In this study, we examined the hepatic anti-steatosis activity of carnosic acid (CA), a phenolic compound of rosemary (Rosmarinus officinalis) leaves, as well as its possible mechanism of action, in a high-fat diet (HFD)-fed mice model. Mice were fed a HFD, or a HFD supplemented with 0.01% (w/w) CA or 0.02% (w/w) CA, for a period of 12 weeks, after which changes in body weight, blood lipid profiles, and fatty acid mechanism markers were evaluated. The 0.02% (w/w) CA diet resulted in a marked decline in steatosis grade, as well as in homeostasis model assessment of insulin resistance (HOMA-IR) index values, intraperitoneal glucose tolerance test (IGTT) results, body weight gain, liver weight, and blood lipid levels (P < 0.05). The expression level of hepatic lipogenic genes, such as sterol regulating element binding protein-1c (SREBP-1c), liver-fatty acid binding protein (L-FABP), stearoyl-CoA desaturase 1 (SCD1), and fatty acid synthase (FAS), was significantly lower in mice fed 0.01% (w/w) CA and 0.02% (w/w) CA diets than that in the HFD group; on the other hand, the expression level of beta-oxidation-related genes, such as peroxisome proliferator-activated receptor alpha (PPAR-alpha), carnitine palmitoyltransferase 1 (CPT-1), and acyl-CoA oxidase (ACO), was higher in mice fed a 0.02% (w/w) CA diet, than that in the HFD group (P < 0.05). In addition, the hepatic content of palmitic acid (C16:0), palmitoleic acid (C16:1), and oleic acid (C18:1) was significantly lower in mice fed the 0.02% (w/w) CA diet than that in the HFD group (P < 0.05). These results suggest that orally administered CA suppressed HFD-induced hepatic steatosis and fatty liver-related metabolic disorders through decrease of de novo lipogenesis and fatty acid elongation and increase of fatty acid beta-oxidation in mice.
Acyl Coenzyme A ; Acyl-CoA Oxidase ; Animals ; Body Weight ; Carnitine O-Palmitoyltransferase ; Carrier Proteins ; Diet ; Diet, High-Fat ; Diterpenes, Abietane ; Fatty Acid Synthetase Complex ; Fatty Acids, Monounsaturated ; Glucose Tolerance Test ; Hand ; Homeostasis ; Insulin Resistance ; Lipogenesis ; Liver ; Mice ; Oleic Acid ; Palmitic Acid ; Phenol ; Plant Extracts ; PPAR alpha ; Stearoyl-CoA Desaturase

The possibility of heterologous expression of human Stearoyl-CoA Desaturase (scd1) was investigated. The scd1 encoding sequence was inserted into the pNZ8149 to generate the pNZ8149-scd1 expression plasmids. Then we introduced the pNZ8149-scd1 construct into the Lactococcus lactis NZ3900 to investigate its enzyme activity. The results show that heterologous expressed SCD1 enzyme resulted in a 92%-169% increase in the C16:1n-7 and a 53-127% increase in the C18:1n-7 (P<0.05). The SCD1 enzyme was capable of producing n-7 fatty acids in Lactococcus lactis efficiently. It also suggests that the fatty acid desaturases can be heterologous expressed in Lactococcus lactis to produce the helpful fatty acids.
Electroporation ; Humans ; Lactococcus lactis ; genetics ; metabolism ; Mutagenesis, Insertional ; Nisin ; pharmacology ; Recombinant Proteins ; biosynthesis ; genetics ; Stearoyl-CoA Desaturase ; biosynthesis ; genetics