Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 REVIEW ARTICLE The Role of Stearoyl-coenzyme A Desaturase 1 in Liver Development, Function, and Pathogenesis Fatemeh Mohammadzadeh1, Vahid Hosseini2, Alireza Alihemmati3, Maghsod Shaaker1, Gholamali Mosayyebi4, Masoud Darabi1, Amir Mehdizadeh5 1Emergency Medicine Research Center Team, Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; 2 Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; 3 Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; 4Liver and Gastrointestinal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 5Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Abstract Stearoyl-coenzyme A desaturase 1 (SCD1) is a microsomal enzyme that controls fatty acid metabolism and is highly expressed in hepatocytes. SCD1 may play a key role in liver development and hepatic lipid homeostasis through promoting monounsaturated protein acylation and converting lipotoxic saturated fatty acids into monounsaturated fatty acids. Imbalanced activity of SCD1 has been implicated in fatty liver induction, inflammation and stress. In this review, the role of SCD1 in hepatic development, function and pathogenesis is discussed. Additionally, emerging novel therapeutic agents targeting SCD1 for the treatment of liver disorders are presented. Keywords: hepatic lipogenesis; hydroxy pyridine; MK-8245; stearoyl-coenzyme A desaturase 1; SCD1 Received: 20 December 2018; Accepted after Revision: 15 January 2019; Published: 06 February 2019 Authors for correspondence: Masoud Darabi, Emergency Medicine Research Center Team, Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Email: darabim@tbzmed.ac.ir; Amir Mehdizadeh, Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Email: mehdizadeha@tbzmed.ac.ir How to cite: Mohammadzadeh F et al. The role of Stearoyl-coenzyme A Desaturase 1 in liver development, function and pathogenesis. J Ren Hepat Disord. 2019;3(1):15–22. Doi: http://dx.doi.org/10.15586/jrenhep.2019.49 Copyright: Mohammadzadeh F et al. License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0 Introduction Stearoyl-coenzyme A desaturase 1 (SCD1) was discovered in 1988 when Ntambi and colleagues identified an mRNA tran- script whose expression was highly induced during adipogenic differentiation (1). SCD1 is an iron-containing lipid- regulating enzyme that is highly expressed in the liver and is the main en- zyme responsible for de novo synthesis of monounsaturated fatty acids (MUFAs). Palmitoyl-CoA and stearoyl-CoA are the main substrates of this enzyme, converting them into palmitoleoyl-CoA and oleoyl-CoA, respectively (2). SCD1 is coded by its gene on the long arm of chromosome 24, in the sub-band 3 of region 24 (3). Promoter activity region is located within the initial 609 bp upstream of transcription initiation site which constitutes a CCAAT-box identified as P U B L I C A T I O N S CODON Journal of Renal and Hepatic Disorders mailto:darabim@tbzmed.ac.ir mailto:mehdizadeha@tbzmed.ac.ir http://dx.doi.org/10.15586/jrenhep.2019.49 http://creativecommons.org/licenses/by/4.0 Mohammadzadeh F et al. Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 16 a cis-element binding site. Sterol regulatory element-binding transcription factor 1 (SREBP-1c), liver X receptor (LXR), peroxisome proliferator-activated receptor alpha (PPAR-α) and CCAAT/enhancer-binding protein alpha (C/EBP-α) are among the most important transcription factors that bind to SCD1 promoter and control its gene expression (4). The pseudogene of SCD1, containing two premature stop codons downstream of the original start codon, is located on the short arm of chromosome 24 in the sub-band 32 of region 11 (5). SCD1 protein is a microsomal enzyme containing four transmembrane domains in which both the N-terminus and C-terminus are located in the cytoplasm (Figure 1). Eight his- tidine residues on the single cytoplasmic loop and C- terminus are conserved and important for desaturase catalytic activ- ity (6). Purified SCD1 protein migrates as a 37 kDa band by SDS gel electrophoresis (7, 8). As fatty acids are important components of phospholipids, triglycerides and esterified cholesterol, changes in SCD1 expression and activity can af- fect membrane stability, lipid metabolism and the amount of adipose tissue; consequent changes may be associated with obesity, fatty liver, cancers, diabetes and atherosclerosis (9). This review provides an overview of the role of SCD1 on var- ious aspects of liver pathophysiology such as development, hepatic lipogenesis and inflammation. It also summarizes the role of novel small molecules targeting SCD1 as potential agents for the treatment of various liver disorders. SCD1 Activity Contributes to Liver Development through Protein Acylation The Wnt family of proteins are signaling molecules that orchestrate numerous homeostatic events from embryonic development to adult tissue function (10). Their malfunc- tion causes various hepatic abnormalities. The products of SCD1 can regulate Wnt trafficking and function through MUFA acylation or lipidation (Figure 2). Monounsaturated fatty acyl moieties render Wnts hydrophobic and insoluble in aqueous environment (11). During the embryonic stage, the inner layer, endoderm, is partitioned into three regions termed as foregut, midgut, and hindgut, with the foregut containing liver precursors. The liver and biliary tracts de- velop from the foregut at the 4th week of gestation (12). The intermediate germ layer, mesoderm, produces Wnt which contributes to the development of hindgut in the posterior endoderm. In the anterior endoderm, however, suppression of Wnt signaling retains foregut fate and allows subsequent development of the liver (13, 14). Overall, Wnt signaling is tightly regulated during embryo development, which is par- ticularly important at the initial stages of liver development. Absence of Wnt signaling activity will result in impaired he- patic development. This is supported by the elevated expres- sion of Wnt downstream core transcription factors during the terminal differentiation of hepatocytes (15). SCD1 shows a determinant role in the in vitro differentia- tion process of human-induced pluripotent stem cells toward hepatic lineage. Inhibition of SCD1 by a selective inhibitor in early stages of in vitro induced differentiation has resulted Figure 1. Stearoyl-coenzyme A desaturase 1 (SCD1) is an iron-containing transmembrane enzyme. SCD1 protein is exclusively localized on the ER membrane with both the N- and C-terminal domains stretched into the cytosol. It has four transmembrane helices (purple cylindrical shapes). The eight histidines (hexagonal shapes) on the single cytoplasmic loop and C-terminus are highly conserved, particularly regions surrounding the di-iron center. The cytosolic domain provides a structural frame for the regioselectivity and stereospecificity of the desaturation reaction (6). Figure 2. Stearoyl-coenzyme A desaturase 1 (SCD1) contributes to liver development and regeneration by modulating Wnt activity. Microsomal SCD1 produces monounsaturated fatty acids that can be attached to Wnts. This process, termed acylation, enables Wnt secretion and activation. Wnt acylation is also a prerequisite for the formation of concentration and activity gradients of Wnts. The Wnt gradients mediate zonal development of liver and regeneration. Stearoyl-coenzyme A Desaturase 1 and liver Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 17 in decreased hepatic markers. In the rescue experiments with the combination of the SCD1 inhibitor and its main product oleate, the effect of inhibitor was strongly reversed (16). Our ongoing in vivo work is to identify the role of SCD1 in the early stages of liver organogenesis and development, espe- cially its role in the formation of a complete liver before birth. Apart from hepatocyte differentiation, Wnt signaling path- way plays a central role in liver zonation (17). Hepatocytes adjacent to portal vein are named periportal hepatocytes (zone 1) and involved in glyconeogenesis and β-oxidation, whereas those near the central vein are called pericentral hepa- tocytes (zone 3) and play a distinct role in drug metabolism and glycolysis. Hepatocytes in zone 2 exhibit an intermediary role having both periportal and pericentral functions. In a re- cent study, a high β-catenin-dependent Wnt signaling activity was observed in zone 3 (17–19). These findings collectively highlight the importance of the SCD1- produced MUFAs in mediating liver development through Wnt regulation. Recent studies using animal models of partial hepatec- tomy have also implicated the direct involvement of Wnt signaling pathway in liver regeneration. The expression and nuclear translocation of β-catenin significantly increase within minutes of hepatectomy and promote hepatocyte pro- liferation rate (20). In acetaminophen-induced liver injury, Wnt/β- catenin not only induces the expression of enzymes involved in drug metabolism such as cytochrome P450 2E1 and cytochrome P450 1A2 but also helps liver regeneration (21, 22). In line with this finding, SCD1 gene expression was increased 3.5-fold in regenerating liver following major liver resection (23). After tissue damage, the residual cells start the repair process (24), and the proliferating cells accumulate several categories of lipids including triglycerides, fatty acids (both saturated and unsaturated), and cholesterol esters (25). These lipids are thought to undergo oxidation and provide the required energy for cell proliferation. In addition, they are the main components of newly synthetized membranes. Besides, these lipids can contribute to various signal trans- duction cascades related to cell proliferation and differentia- tion such as Wnt and hedgehog signaling pathways (26). It is hypothesized that MUFAs produced by SCD1 not only pro- vide metabolic energy source and structural components, but also promote protein acylation–mediated signaling, which are essential for liver regeneration. SCD1 Prevents Lipotoxicity and Controls Hepatic Lipogenesis Palmitic acid and stearic acid are the major de novo synthe- sized lipotoxic saturated fatty acids (SFAs) in the liver. SCD1 mediates the addition of a double bond to the saturated carbon chain. On one hand, SCD1 activity attenuates SFAs lipotoxic effects through their conversion into the MUFAs palmitoleic acid and oleic acid (27). On the other hand, SCD1 generates unsaturated fatty acids serving as rate-limiting substrates for lipogenesis (28). Thus, an improper increase in its activity may cause hepatic lipid accumulation. Despite oleate being the major dietary MUFA, SCD1 expression is highly regulated in response to developmen- tal, dietary, environmental, and hormonal factors. De novo synthesized MUFAs are the preferred substrates for neutral hepatic lipid synthesis including triglycerides and cholesterol ester. SCD1 inhibition protects against high-fat high-carbo- hydrate diet, leptin-deficiency-induced obesity, and hepatic steatosis (29). Leptin-deficient mice exhibit SCD1 overex- pression causing palmitoleate and oleate accumulation in liver as fat droplets. Recent studies on high-carbohydrate-fed rats have revealed that deficiency in SCD1 decreased lipid synthesis, elevated fatty acid oxidation and thermogenesis, and insulin susceptibility in different tissues, especially in the liver (30). Sampath et al. (31) showed that stearate-rich diet causes SCD1 induction and hepatic lipid accumulation in wild-type mice but not in scd1-/- mice. However, in scd1-/- mice, stearate does not induce genes involved in lipogenesis. Additionally, sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor coactiva- tor-1 (PGC-1) transcription factors, which are necessary mediators for pro-lipogenic activities of saturated fatty acids (SFAs), were downregulated in scd1-/- mice. Instead, fatty acid oxidation genes such as carnitine palmitoyltransferase-1 (CPT-1) were induced, resulting in hepatic glycogen deple- tion. Lui et al. (32), in a study on zinc finger transcription factor knockout mouse model, showed a significant decrease in SCD1 expression and triglyceride accumulation compared to controls. Binding of this transcription factor to SCD1 pro- moter in hepatocytes was also reported in this study, indicat- ing its critical role in the activation of SCD1 expression. The role of SCD1 in gut microbiota-dependent hepatic lipogenesis has been studied by Singh et al. (28). They re- ported that mice with deficient Toll-like receptor-5, which is expressed in gut epithelial cells and plays an important role in microbiota homeostasis, exhibit a microbiota-dependent metabolic syndrome with elevated hepatic lipogenesis, SCD1 expression and activity, and hepatic neutral lipids accumula- tion with a high oleate and palmitoleate content. Furthermore, the expression level of SCD1 and fatty acid synthase along with endoplasmic reticulum (ER) stress markers was downregulated in response to the inhibition of poly ADP-ribose polymerase (PARP), which is overexpressed in long-term high-fat high-sucrose diet in mice, indicating the PARP-SCD1 interaction as a major mechanism in the in- duction of non-alcoholic fatty liver disease (33). The role of SCD1 in an alcoholic fatty liver disease model was studied by Louinis et al. (34). In that study, mice fed with a low-MUFA diet containing 5% ethanol for 10 days and a single ethanol gavage (5 g/kg) developed severe hepatic injury. Liver-specific Scd1-knock-out (SCD1-LKO) mice were resistant to such hepatic injury. Mohammadzadeh F et al. Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 18 In a recent cross-sectional clinical study, it has been shown that the serum SCD1 activity index is significantly related to the risk of non-alcoholic fatty liver disease in patients with primary dyslipidemia (35). Of course, while interpreting these data, it should be noted that the index of serum SCD1 activity is not solely determined by the liver. In this field, the Ntambi laboratory has recently shown that hepatic tri- glyceride accumulation in mice may be induced by increased hepatic trafficking of MUFAs originating from non-liver tissues (36). The latter finding further supports the hypoth- esis that fine-tuning of hepatic SCD1 activity is critical in variable metabolic states. SCD1 Modulates Hepatic Inflammation and Oxidative Stress Current evidence indicates the regulatory role of fatty acids in cellular inflammation. SCD1 plays an important role in maintaining the balance between SFAs and MUFAs. Toxic accumulation of SFAs that are reflected as MUFAs/SFAs imbalance leads to activation of oxidative stress imbalance in hepatocytes (37, 38). SFAs mediate cellular inflammatory response through binding to Toll-like receptor-4, CD14, and myeloid differentiation protein-2, causing increased produc- tion of bacterial lipopolysaccharides, oxidized phospholip- ids, and oxidized low-density lipoproteins through intestinal microbiota modification (39). These findings support the hy- pothesis that SCD1 activity may be protective against SFA- induced oxidative stress and hepatic inflammation. Lu et al. (40) reported that IKK2 (an activator of NFκB) activation can induce hepatic SCD1 overexpression and triglyceride accumulation in mouse. However, such activation decreased the expression of oxidative stress and prevented hepatic in- flammation and fibrosis. Paradoxically, there is evidence that increased SCD1 activity may contribute to inflammation and oxidative stress. In the high-carbohydrate or high-sucrose, very-low-fat diet, oleate supplementation leads to decreased hepatic injury and oxidative stress in mice with liver-specific SCD1-LKO (41). A high-fructose diet in female C57BL/6J mice also induced oxidative stress characterized by hepatic SCD1 overexpression and elevation of inducible nitric oxide synthase levels (42). Ochi et al. (43) also showed the associa- tion of SCD1 with the development of non-alcoholic steato- hepatitis (NASH) under induced stress condition. Indeed, a knockout C57BL/6 mice model with a low expression and activity of SCD1 showed lower hepatic lipid accumulation and steatosis following tunicamycin-induced ER stress than the wild-type mice with ER stress. Overall, as illustrated in Figure 3, balanced activity of SCD1 is important for stabilizing the ratio of unsaturated to saturated fatty acids. An increase in this ratio can lead to lipid accumulation and a decrease in this ratio is associated with lipotoxicity. A rise in both lipid accumulation and lipotox- icity may lead to hepatic inflammation and oxidative stress. SCD-1 as a Potential Therapeutic Target The aforementioned studies highlight the significant role of SCD1 activity in hepatic pathophysiology. Therapeutic strategies targeting SCD1 may have applications in man- aging liver disorders. Several studies have examined small molecule inhibitors in this regard. The following sections review recent advances in small molecule SCD1 inhibitors and their potential therapeutic application in hepatic disor- ders (Table 1). MK-8245 SCD1 enzyme is expressed in many cell types of the body. Therefore, potential SCD1 inhibitors for the treatment of liver diseases will have a lot of side effects although they might be highly selective toward SCD1. For example, SCD1- knockout rodent models and SCD1 inhibitor–treated rats de- velop severe skin and eye abnormalities (44, 45). Therefore, liver-specific targeting of SCD1 may be an effective strategy for the treatment of liver-related disorders. One such in- hibitor is MK-8245 (46). It has a transporting element that specifically interacts with heptocytes via the liver-specific organic anion transporting polypeptides. Administration of MK-8245 to mice fed with a high-fat diet did not reduce food intake. Despite this, a reduction in liver steatosis and a decrease in liver triglyceride levels were observed. MK-8245 also exhibited anti-diabetic and anti-dyslipidemic proper- ties. Administration of MK-8245 to individuals with type 2 diabetes mellitus in a phase II clinical trial showed no se- rious adverse events (47). MK-8245 may also be an option for anti-hepatitis C virus (HCV) therapy as evaluated using recombinant HCV culture systems (48). The potential thera- peutic effects of this compound on liver diseases are yet to be clinically examined. Figure 3. Stearoyl-coenzyme A desaturase 1 (SCD1) activity is associated with normal liver function. The schematic balance represents that the equilibrium between saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) is important in the physiological state. The loss of this equilibrium is due to overactivity and underactivity of SCD1 in hepatic lipid accumulation and lipotoxicity, respectively. Stearoyl-coenzyme A Desaturase 1 and liver Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 19 Hydroxy pyridone Another compound that was used for targeted liver SCD1 inhibition is 4-hydroxy pyridine (49). According to the pharmacokinetic analysis, this SCD1 inhibitor had a sig- nificantly higher concentration in liver than in plasma and eyelid. It showed a good potency in reducing the mouse liver ratio of palmitoleate to palmitate as a biomarker for SCD1 activity (49). Pyridazine derivative A piperazine-based SCD-1 inhibitor, N-(2-hydroxy-2- phenylethyl)-6-[4-(2 methylbenzoyl)piperidin-1-yl]pyridaz- ine-3-carboxamide, has been shown to produce beneficial effects in experimental modes of NASH (50, 51). When administered orally for 8 weeks, once daily, triglyceride accumulation in the liver was reduced by 80% from the fourth week. It also attenuated the increase of aspartate aminotransferase and alanine transaminase by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degen- eration, and inflammatory cell infiltration were also amelio- rated after the treatment (50). Thiazole analogs Current evidence shows that host cell lipid homeostasis plays a critical role in the pathogenesis of HCV by facilitat- ing the formation of viral membrane-associated replication complex. Since inhibiting lipogenesis has a negative effect on virus proliferation, inhibiting the lipid synthesis enzyme SCD1 is a potential strategy for HCV treatment (52, 53). Lyn et al. (54) showed that the thiazole compound MF-152 can repress HCV infection in human hepatoma cells by modify- ing membrane functions which are required for HCV rep- lication. Cell imaging studies showed that the inability of viral RNAs to interact with modified membranes exposes them to degradation by endogenous nucleases. This process ultimately prevents the formation of HCV viral complexes and arrests HCV replication. Thiazole-4-acetic acid derivative Another potent liver-selective SCD1 inhibitor, compound 48 (a thiazole-4-acetic acid derivative), has recently been discovered through high-throughput screening efforts fol- lowing an ex vivo assay approach on mice liver and eyelids (55). Administration of compound 48 to mice fed a high- fat diet for 43 days improved glucose tolerance and de- creased body weight without adverse effects on skin or eyes. Furthermore, compound 48 significantly attenuated hepatic triglyceride accumulation in rats fed a high-sucrose, very- low-fat diet (55). These findings suggest that compound 48 may have clinical benefits in the treatment of diabetes, he- patic steatosis, and obesity through targeting SCD1 activity in liver. Conclusion SCD1, one of the predominantly expressed enzymes in the liver, is a major factor in fatty acid metabolism. It plays a regulatory role in posttranslational protein modifica- tions via protein acylation. Wnts play an important role in hepatic differentiation, zonation, and regeneration. The Wnts pathway, at least in part, is regulated by SCD1- mediated palmitoleoylation and oleoylation. In addition, SCD1 is crucial for SFA detoxification and MUFA produc- tion. SFAs overproduction induces hepatic inflammation and oxidative stress, and SCD1 attenuates these effects via monounsaturation of SFAs. Meanwhile, de novo produced MUFAs promote and participate in cellular lipogenesis and their overproduction can lead to hepatic lipid accu- mulation. Targeting SCD1 as a novel therapeutic approach may be beneficial in liver disorders. In this regard, several studies have tested small molecule inhibitors of SCD1 Table 1. Stearoyl-coenzyme A desaturase 1 small molecule inhibitors with potential applications for hepatic diseases. Compound Liver-selective Therapeutic application Current evidence Reference MK-8245 + Diabetes, dyslipidemia, HCV Preclinical/animal/ phase II clinical trial (46, 48) Hydroxy pyridone + Dyslipidemia- In vivo (49) N-(2-hydroxy-2-phenylethyl)-6-[4- (2-methylbenzoyl)piperidin-1-yl] pyridazine-3-carboxamide - Reduction in triglyceride accumulation in NASH In vivo (50, 51) Thiazole analogs - HCV infection In vitro (54) Thiazol-4-acetic acid derivatives + Diabetes, hepatic steatosis and obesity In vivo (55) HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; OATP, organic-anion-transporting polypeptide. Mohammadzadeh F et al. Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 20 in vitro and in vivo, which opens a promising point of view in the treatment of liver metabolic diseases. Acknowledgments This study was supported by a grant (No. 5.4.9705) from the Emergency Medicine Research Team at Tabriz University of Medical Sciences. Conflict of interest The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article. References 1. Ntambi JM, Buhrow SA, Kaestner KH, Christy RJ, Sibley E, Kelly TJ, et al. Differentiation-induced gene expression in 3T3- L1 preadipocytes. Characterization of a differentially expressed gene encoding stearoyl-CoA desaturase. J Biol Chem [Internet]. 1988 Nov 25;263(33):17291–300. Available from (accessed 25.12.18.): http://www.ncbi.nlm.nih.gov/pubmed/2903162 2. Flowers MT, Ntambi JM. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol. 2008 Jun;19(3):248–56. https://doi.org/10.1097/MOL.0b013e 3282f9b54d 3. Arregui M, Buijsse B, Stefan N, Corella D, Fisher E, di Giuseppe R, et al. Heterogeneity of the Stearoyl-CoA de- saturase-1 (SCD1) gene and metabolic risk factors in the EPIC-Potsdam study. PLoS One. 2012;7:e48338. https://doi. org/10.1371/ journal.pone.0048338 4. Mauvoisin D, Charfi C, Lounis AM, Rassart E, Mounier C. Decreasing stearoyl-CoA desaturase-1 expression inhib- its β- catenin signaling in breast cancer cells. Cancer Sci. 2013 Jan;104(1):36–42. Available from: https://doi.org/10.1111/ cas.12032 5. Zhang L, Ge L, Tran T, Stenn K, Prouty SM. Isolation and characterization of the human stearoyl-CoA desaturase gene promoter: Requirement of a conserved CCAAT cis-element. Biochem J. 2001;357:183–93. https://doi.org/10.1042/bj3570183 6. Bai Y, McCoy JG, Levin EJ, Sobrado P, Rajashankar KR, Fox BG, et al. X-ray structure of a mammalian stearoyl-CoA de- saturase. Nature. 2015 Aug;524(7564): 252–6. Available from: https://doi.org/10.1038/nature14549 7. Mehdizadeh A, Fayezi S, Darabi M. SCD (stearoyl- CoA desaturase (delta-9-desaturase)). Atlas Genet Cytogenet Oncol Haematol. 2016;20(2):77–80. https://doi. org/10.4267/2042/62515 8. Kim YC, Gomez FE, Fox BG, Ntambi JM. Differential reg- ulation of the stearoyl-CoA desaturase genes by thiazolidin- ediones in 3T3-L1 adipocytes. J Lipid Res [Internet]. 2000 Aug;41(8):1310–16. Available from (accessed 25.12.18.): http:// www.ncbi.nlm.nih.gov/pubmed/10946019 9. Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim H-J, et al. Stearoyl-CoA Desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein- 1c- dependent and -independent mechanisms. J Biol Chem. 2004 Jun;279(24):25164–71. https://doi.org/10.1074/jbc. M40 2781200 10. Steinhart Z, Angers S. Wnt signaling in development and tis- sue homeostasis. Development. 2018;145(11):1–8. https://doi. org/10.1242/dev.146589 11. Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science. 2012 Jul;337(6090):59–64. https://doi.org/10.1126/science.1222879 12. Sekine K, Takebe T, Taniguchi H. Liver regeneration using cul- tured liver bud. Methods Mol Biol. 2017;1597:207–16. https:// doi.org/10.1007/978-1-4939-6949-4_15 13. Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman JR, Zaret KS. Hepatic specification of the gut endoderm in vitro: Cell signaling and transcriptional control. Genes Dev. 1996 Jul;10(13):1670–82. https://doi.org/10.1101/gad.10.13.1670 14. Lokmane L, Haumaitre C, Garcia-Villalba P, Anselme I, Schneider-Maunoury S, Cereghini S. Crucial role of vHNF1 in vertebrate hepatic specification. Development. 2008 Aug;135(16):2777–86. https://doi.org/10.1242/dev.023010 15. Lemaigre FP. Mechanisms of liver development: Concepts for understanding liver disorders and design of novel ther- apies. Gastroenterology. 2009 Jul;137(1):62–79. https://doi. org/10.1053/j.gastro.2009.03.035 16. Rahimi Y, Mehdizadeh A, Nozad Charoudeh H, Nouri M, Valaei K, Fayezi S, et al. Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl-CoA de- saturase 1 activity. Dev Growth Differ. 2015 Dec;57(9):667–74. Available from: https://doi.org/10.1111/dgd.12255 17. Schröder E, Höhme S, Böttger J, Aleithe S, Gebhardt R, Matz-Soja M. Zonation of Morphogens in the adult liver – Crosstalk be- tween Hh and Wnt/β-Catenin signaling. Z Gastroenterol. 2018 Jan;56(01):E2–89. https://doi.org/10.1055/s-0037-1612748 18. Brosch M, Kattler K, Herrmann A, von Schönfels W, Nordström K, Seehofer D, et al. Epigenomic map of human liver reveals principles of zonated morphogenic and meta- bolic control. Nat Commun. 2018 Oct;9(1):4150. https://doi. org/10.1038/s41467-018-06611-5 19. Preziosi M, Okabe H, Poddar M, Singh S, Monga SP. Endothelial Wnts regulate β-catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt-Wnt situation. Hepatol Commun. 2018 Jul;2(7):845–60. https://doi.org/10.1002/ hep4.1196 20. Nelsen CJ, Rickheim DG, Timchenko NA, Stanley MW, Albrecht JH. Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth in vivo. Cancer Res. 2001 Dec;61(23):8564–8. 21. Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ. Wnt/β- catenin activation promotes prostate tumor progression in a mouse model. Oncogene. 2011 Apr;30(16):1868–79. https://doi. org/10.1038/onc.2010.560 22. Dadhania VP, Bhushan B, Apte U, Mehendale HM. Wnt/β- Catenin signaling drives thioacetamide-mediated heteroprotec- tion against acetaminophen-induced lethal liver injury. Dose Response. 15(1):1559325817690287. https://doi.org/10.1177/ 1559325817690287 23. Xu C, Lin F, Qin S. Relevance between lipid metabolism- associated genes and rat liver regeneration. Hepatol Res. 2008 Aug;38(8): 825–37. https://doi.org/10.1111/j.1872-034X. 2008. 00345.x 24. Forbes SJ, Newsome PN. Liver regeneration—mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol. 2016;13(8):473–85. https://doi.org/10.1038/nrgastro.2016.97 25. Bellet MM, Masri S, Astarita G, Sassone-Corsi P, Della Fazia MA, Servillo G. Histone deacetylase SIRT1 controls prolif- eration, circadian rhythm, and lipid metabolism during liver http://www.ncbi.nlm.nih.gov/pubmed/2903162 https://doi.org/10.1097/MOL.0b013e3282f9b54d https://doi.org/10.1097/MOL.0b013e3282f9b54d https://doi.org/10.1371/journal.pone.0048338 https://doi.org/10.1371/journal.pone.0048338 https://doi.org/10.1111/cas.12032 https://doi.org/10.1111/cas.12032 https://doi.org/10.1042/bj3570183 https://doi.org/10.1038/nature14549 https://doi.org/10.4267/2042/62515 https://doi.org/10.4267/2042/62515 http://www.ncbi.nlm.nih.gov/pubmed/10946019 http://www.ncbi.nlm.nih.gov/pubmed/10946019 https://doi.org/10.1074/jbc.M402781200 https://doi.org/10.1074/jbc.M402781200 https://doi.org/10.1242/dev.146589 https://doi.org/10.1242/dev.146589 https://doi.org/10.1126/science.1222879 https://doi.org/10.1007/978-1-4939-6949-4_15 https://doi.org/10.1007/978-1-4939-6949-4_15 https://doi.org/10.1101/gad.10.13.1670 https://doi.org/10.1242/dev.023010 https://doi.org/10.1053/j.gastro.2009.03.035 https://doi.org/10.1053/j.gastro.2009.03.035 https://doi.org/10.1111/dgd.12255 https://doi.org/10.1055/s-0037-1612748 https://doi.org/10.1038/s41467-018-06611-5 https://doi.org/10.1038/s41467-018-06611-5 https://doi.org/10.1002/hep4.1196 https://doi.org/10.1002/hep4.1196 https://doi.org/10.1038/onc.2010.560 https://doi.org/10.1038/onc.2010.560 https://doi.org/10.1177/1559325817690287 https://doi.org/10.1177/1559325817690287 https://doi.org/10.1111/j.1872-034X.2008.00345.x https://doi.org/10.1111/j.1872-034X.2008.00345.x https://doi.org/10.1038/nrgastro.2016.97 Stearoyl-coenzyme A Desaturase 1 and liver Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 21 regeneration in mice. J Biol Chem. 2016;291(44):23318–29. https://doi.org/10.1074/jbc.M116.737114 26. Kohjima M, Tsai T-H, Tackett BC, Thevananther S, Li L, Chang BH-J, et al. Delayed liver regeneration after partial hepa- tectomy in adipose differentiation related protein-null mice. J Hepatol. 2013 Dec;59(6):1246–54. https://doi.org/10.1016/j. jhep.2013.07.025 27. Collins JM, Neville MJ, Hoppa MB, Frayn KN. De novo lipogenesis and stearoyl-CoA desaturase are coordinately reg- ulated in the human adipocyte and protect against palmitate- induced cell injury. J Biol Chem. 2010;285:6044–52. https://doi. org/10.1074/jbc.M109.053280 28. Singh V, Chassaing B, Zhang L, San Yeoh B, Xiao X, Kumar M, et al. Microbiota-dependent hepatic lipogenesis mediated by Stearoyl CoA Desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab. 2015 Dec;22(6):983–96. https://doi.org/10.1016/j.cmet.2015.09.028 29. Miyazaki M, Sampath H, Liu X, Flowers MT, Chu K, Dobrzyn A, et al. Stearoyl-CoA desaturase-1 deficiency atten- uates obesity and insulin resistance in leptin-resistant obese mice. Biochem Biophys Res Commun. 2009 Mar;380(4):818–22. https://doi.org/10.1016/j.bbrc.2009.01.183 30. Miyazaki M, Flowers MT, Sampath H, Chu K, Otzelberger C, Liu X, et al. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and he- patic steatosis. Cell Metab. 2007 Dec;6(6):484–96. https://doi. org/10.1016/j.cmet.2007.10.014 31. Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl- CoA desaturase-1 mediates the pro-lipogenic effects of di- etary saturated fat. J Biol Chem. 2007 Jan;282(4): 2483–93. Available from: https://doi.org/10.1074/jbc.M610158200 32. Liu G, Zhou L, Zhang H, Chen R, Zhang Y, Li L, et al. Regulation of hepatic lipogenesis by the zinc finger pro- tein Zbtb20. Nat Commun. 2017 Mar;8:14824. https://doi. org/10.1038/ncomms14824 33. Gariani K, Ryu D, Menzies KJ, Yi H-S, Stein S, Zhang H, et al. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J Hepatol. 2017;66(1):132–41. https://doi.org/10.1016/j.jhep. 2016.08.024 34. Lounis MA, Escoula Q, Veillette C, Bergeron K-F, Ntambi JM, Mounier C. SCD1 deficiency protects mice against ethanol- induced liver injury. Biochim Biophys Acta. 2016;1861(11): 1662–70. https://doi.org/10.1016/j.bbalip.2016.07.012 35. Amor AJ, Cofán M, Mateo-Gallego R, Cenarro A, Civeira F, Ortega E, et al. Dietary polyunsaturated fatty acids mediate the inverse association of stearoyl-CoA desaturase activity with the risk of fatty liver in dyslipidaemic individuals. Eur J Nutr. 2018 Apr; Available from: https://doi.org/10.1007/s00394-018-1691-4 36. Bond LM, Ntambi JM. UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver. J Lipid Res. 2018 Feb;59(2):224–36. Available from: https://doi.org/10.1194/jlr.M078469 37. Wek RC, Anthony TG. Obesity: Stressing about unfolded pro- teins. Nat Med. 2010 Apr;16(4):374–6. https://doi.org/10.1038/ nm0410-374 38. Ron D, Walter P. Signal integration in the endoplasmic retic- ulum unfolded protein response. Nat Rev Mol Cell Biol. 2007 Jul;8(7):519–29. https://doi.org/10.1038/nrm2199 39. Rocha DM, Caldas AP, Oliveira LL, Bressan J, Hermsdorff HH. Saturated fatty acids trigger TLR4-mediated inflamma- tory response. Atherosclerosis. 2016 Jan;244:211–5. https://doi. org/10.1016/j.atherosclerosis.2015.11.015 40. Lu H, Lei X, Zhang Q. Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis. BMC Gastroenterol. 2015 Jul;15:94. https://doi.org/10.1186/ s12876-015-0325-z 41. Liu X, Burhans MS, Flowers MT, Ntambi JM. Hepatic oleate regulates liver stress response partially through PGC-1α dur- ing high-carbohydrate feeding. J Hepatol. 2016;65(1):103–12. https://doi.org/10.1016/j.jhep.2016.03.001 42. Choi Y, Abdelmegeed MA, Song B-J. Diet high in fructose pro- motes liver steatosis and hepatocyte apoptosis in C57BL/6J fe- male mice: Role of disturbed lipid homeostasis and increased oxidative stress. Food Chem Toxicol. 2017 May;103:111–21. https://doi.org/10.1016/j.fct.2017.02.039 43. Ochi T, Munekage K, Ono M, Higuchi T, Tsuda M, Hayashi Y, et al. Patatin-like phospholipase domain-containing protein 3 is involved in hepatic fatty acid and triglyceride metabolism through X-box binding protein 1 and modulation of endo- plasmic reticulum stress in mice. Hepatol Res. 2016 May;46(6): 584–92. https://doi.org/10.1111/hepr.12587 44. Miyazaki M, Man WC, Ntambi JM. Targeted disruption of stearoyl-CoA desaturase1 gene in mice causes atrophy of seba- ceous and meibomian glands and depletion of wax esters in the eyelid. J Nutr. 2001 Sep;131(9):2260–8. Available from: https:// doi.org/10.1093/jn/131.9.2260 45. Ramtohul YK, Black C, Chan C-C, Crane S, Guay J, Guiral S, et al. SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors. Bioorg Med Chem Lett. 2010 Mar;20(5):1593–7. https://doi.org/10.1016/j.bmcl.2010. 01.083 46. Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, et al. Development of a liver-targeted stearoyl- CoA desaturase (SCD) inhibitor (MK-8245) to establish a ther- apeutic window for the treatment of diabetes and dyslipidemia. J Med Chem. 2011 Jul;54(14):5082–96. https://doi.org/10.1021/ jm200319u 47. Merck Sharp & Dohme Corp. A study to assess the safety and efficacy of MK8245 in patients with type 2 diabetes mel- litus and inadequate glycemic control (MK8245-005 AM2) [Internet]. ClinicalTrials.gov Web Site. 2019. Available from (accessed 25.12.18.): https://clinicaltrials.gov/ct2/show/study/ NCT00846391 48. Nio Y, Hasegawa H, Okamura H, Miyayama Y, Akahori Y, Hijikata M. Liver-specific mono-unsaturated fatty acid syn- thase-1 inhibitor for anti-hepatitis C treatment. Antiviral Res. 2016 Aug;132:262–7. Available from: https://doi.org/10.1016/j. antiviral.2016.07.003 49. Sun S, Zhang Z, Raina V, Pokrovskaia N, Hou D, Namdari R, et al. Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects. Bioorg Med Chem Lett. 2014 Jan;24(2):526–31. https://doi.org/10.1016/j.bmcl. 2013. 12.035 50. Uto Y, Ogata T, Kiyotsuka Y, Ueno Y, Miyazawa Y, Kurata H, et al. Novel benzoylpiperidine-based stearoyl-CoA desatu- rase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl) piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyrid- in-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats. Bioorg Med Chem Lett. 2010 Jan;20(1):341–5. https://doi.org/10.1016/j.bmcl.2009.10.101 51. Kurikawa N, Takagi T, Wakimoto S, Uto Y, Terashima H, Kono K, et al. A novel inhibitor of stearoyl-CoA desaturase-1 at- tenuates hepatic lipid accumulation, liver injury and inflammation https://doi.org/10.1074/jbc.M116.737114 https://doi.org/10.1016/j.jhep.2013.07.025 https://doi.org/10.1016/j.jhep.2013.07.025 https://doi.org/10.1074/jbc.M109.053280 https://doi.org/10.1074/jbc.M109.053280 https://doi.org/10.1016/j.cmet.2015.09.028 https://doi.org/10.1016/j.bbrc.2009.01.183 https://doi.org/10.1016/j.cmet.2007.10.014 https://doi.org/10.1016/j.cmet.2007.10.014 https://doi.org/10.1074/jbc.M610158200 https://doi.org/10.1038/ncomms14824 https://doi.org/10.1038/ncomms14824 https://doi.org/10.1016/j.jhep.2016.08.024 https://doi.org/10.1016/j.jhep.2016.08.024 https://doi.org/10.1016/j.bbalip.2016.07.012 https://doi.org/10.1007/s00394-018-1691-4 https://doi.org/10.1194/jlr.M078469 https://doi.org/10.1038/nm0410-374 https://doi.org/10.1038/nm0410-374 https://doi.org/10.1038/nrm2199 https://doi.org/10.1016/j.atherosclerosis.2015.11.015 https://doi.org/10.1016/j.atherosclerosis.2015.11.015 https://doi.org/10.1186/s12876-015-0325-z https://doi.org/10.1186/s12876-015-0325-z https://doi.org/10.1016/j.jhep.2016.03.001 https://doi.org/10.1016/j.fct.2017.02.039 https://doi.org/10.1111/hepr.12587 https://doi.org/10.1093/jn/131.9.2260 https://doi.org/10.1093/jn/131.9.2260 https://doi.org/10.1016/j.bmcl.2010.01.083 https://doi.org/10.1016/j.bmcl.2010.01.083 https://doi.org/10.1021/jm200319u https://doi.org/10.1021/jm200319u https://clinicaltrials.gov/ct2/show/study/NCT00846391 https://clinicaltrials.gov/ct2/show/study/NCT00846391 https://doi.org/10.1016/j.antiviral.2016.07.003 https://doi.org/10.1016/j.antiviral.2016.07.003 https://doi.org/10.1016/j.bmcl.2013.12.035 https://doi.org/10.1016/j.bmcl.2013.12.035 https://doi.org/10.1016/j.bmcl.2009.10.101 Mohammadzadeh F et al. Journal of Renal and Hepatic Disorders 2019; 3(1): 15–22 22 in model of nonalcoholic steatohepatitis. Biol Pharm Bull. 2013;36(2):259–67. https://doi.org/10.1248/bpb.b12-00702 52. Pezacki JP, Singaravelu R, Lyn RK. Host-virus interactions during hepatitis C virus infection: A complex and dynamic mo- lecular biosystem. Mol Biosyst. 2010 Jul;6(7):1131–42. https:// doi.org/10.1039/b924668c 53. Herker E, Ott M. Unique ties between hepatitis C virus repli- cation and intracellular lipids. Trends Endocrinol Metab. 2011 Jun;22(6):241–8. Available from: https://doi.org/10.1016/j.tem. 2011. 03.004 54. Lyn RK, Singaravelu R, Kargman S, O’Hara S, Chan H, Oballa R, et al. Stearoyl-CoA desaturase inhibition blocks formation of hepatitis C virus-induced specialized membranes. Sci Rep. 2014 Apr;4:4549. https://doi.org/10.1038/srep04549 55. Iida T, Ubukata M, Mitani I, Nakagawa Y, Maeda K, Imai H, et al. Discovery of potent liver-selective stearoyl-CoA desatu- rase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity. Eur J Med Chem. 2018 Oct;158:832–52. https://doi.org/10.1016/j. ejmech. 2018.09.003 https://doi.org/10.1248/bpb.b12-00702 https://doi.org/10.1039/b924668c https://doi.org/10.1039/b924668c https://doi.org/10.1016/j.tem.2011.03.004 https://doi.org/10.1016/j.tem.2011.03.004 https://doi.org/10.1038/srep04549 https://doi.org/10.1016/j.ejmech.2018.09.003 https://doi.org/10.1016/j.ejmech.2018.09.003