Enzymes with properties of the class 1 α-1,2-mannosidases have also been purified from plants136 and from hen oviduct,137 but these have not yet been cloned. They are both inhibited by 1-deoxymannojirimycin, do not utilize p-nitrophenyl-α-d-mannopyranoside as substrate, but unlike other class 1 enzymes they do not require Ca2+ for activity. 1. Several statins have been offered since then, including lovastatin, pravastatin, and simvastatin, which are obtained after fungal fermentation and are known as type 1 statins, while fluvastatin, rosuvastatin, and atorvastatin are fully synthetic inhibitors and correspond to type 2 statins. Penicillium citrinum Thom, U.S.D.A. In February 1979, Merck had isolated a statin very similar to compactin, called mevinolin from the fungus Aspergillus terreus. Therefore, cerivastatin was voluntarily withdrawn worldwide in August 2001 (USFDA, 2001). Lovastatin and mevastatin are synthesized via polyketide pathways. Patients with CVD consuming red yeast rice showed a decreased incidence of nonfatal myocardial infarction or death from cardiac causes compared to placebo [115]. Australian pathologist Howard Florey and British biochemist Ernst Boris Chain isolated and purified penicillin in… Note the drops of exudate (extrolites) which have formed on the surface. Feeding experiments revealed that the decene ring moiety of lovastatin (6) is derived from nine molecules of acetate units with additional methyl groups at positions 6 and 2′, which are derived from methionine. In contrast to aromatic polyketide biosynthesis in fungi, the assembled nonaketide carbon chain is almost fully reduced before the cyclization, which proceeds possibly by a biological Diels–Alder reaction to afford the correct ring system with the right configuration.68 Also, the presence of a methyl group derived from methionine indicated the involvement of methylation of a polyketomethylene intermediate before cyclization by PKS. The success of statins lies not only in their remarkable capability to reduce lipid levels, but also in their cholesterol-independent pleiotropic effects. It now appears that lovC-type proteins are a common feature of HR PKS systems in fungi, although by no means ubiquitous. Interestingly, the MT domain resides in the middle of the PKS. Currently, there are seven statins available for clinical use: lovastatin (1987), simvastatin (1988), pravastatin (1991), fluvastatin (1994), atorvastatin (1997), rosuvastatin (2003), and pitavastatin (2009). Okay, here it is. LNKS itself is too difficult to work with, so Tang and coworkers cloned individual catalytic domains and expressed these in E. coli.30 Two didomains consisting of the KS–AT and ACP–C regions, and three monodomains (AT, ACP, and C) were successfully expressed as soluble proteins. Main page > Index of descriptions > Previous description > Penicillium > Next description Penicillium. The requirement for two PKSs is evident in the gene clusters associated with 19a and 19b biosynthesis where two PKS genes are found. Penicillium citrinum is already known for producing mycotoxin citrinin and cellulose digesting enzymes like cellulase and endoglucanase, as well as xylulase. The levels of lovastatin and other monacolins present in red yeast extracts from 12 proprietary sources varied considerably and some contained the nephrotoxicant citrinin [120]. An excellent Mycology site created by the University of Adelaide in Australia. The results suggested the presence of homologous PKS genes responsible for each lovastatin-related compound’s biosynthesis. Penicillium citrinum: The colourless (hyaline) mycelium is seen at the periphery of the colony. Timeline: history of statins. - long metulae and the somewhat shorter phialides are clearly distinguishable in this photograph. Any errors mine alone. The findings regarding the effectiveness of red yeast rice are encouraging, but improved standardization and oversight are essential before general clinical use can be considered [121]. The presence of lovastatin (monacolin K) in red yeast rice supplements led the Food and Drug Administration of the United States to consider these supplements to be a drug and to restrict their sales. The genus has major importance in the natural environment as well as food and drug production … Penicillium citrinum is an anamorph, mesophilic fungus species of the genus of Penicillium which produces tanzawaic acid A-D, ACC, Mevastatin, Quinocitrinine A, Quinocitrinine B, and nephrotoxic citrinin. 1976; From: Applied Mycology and Biotechnology, 2004, Raghubir P. Sharma, in Handbook of Hazardous Materials, 1993. Whether this applies more broadly to other plants is not known. Thus lovastatin was the first commercial statin introduced into the market. Other minor adverse events associated with statin treatment include hemorrhagic stroke, cancers, depression, liver enzyme elevation, renal dysfunction and arthritis have been reported. Over 20 are mentioned regularly as found in the indoor environment {1056, 470, 2694}. Citrinin has been reported as a nonmutagenic mycotoxin, although some authors have pointed out that it can cause chromosomal abnormalities in bone marrow cells of mammals. Penicillium citrinum is already known for producing mycotoxin citrinin and cellulose digesting enzymes like cellulase and endoglucanase, ... ratory taxon that gained importance after discovery of. We use cookies to help provide and enhance our service and tailor content and ads. Recently, a further example of the effect of a lovC-type protein on programing of a fungal PKS has been described. The most frequently identified species within Penicillium were P. citrinum and P. rubens. The timeline of statin development is shown in Fig. It will be interesting to determine whether the catalytic function and the structure of these enzymes differ significantly from the other class 1 α-1,2-mannosidases. EMBO J. (Click Icon To redirect). A.C. Liwa, ... C.R. HMGR inhibitors have subsequently been isolated from Pleurotus, Monascus, Paecilomyces, Trichoderma, Scopulariopsis, Doratomyces fungal genera as well as several yeast including Candida cariosilignicola and Pichia labacensis[50–53]. The precise mechanism behind statin-induced myopathy has not been fully understood, but may include on-target modulation contributing to the alteration of muscle cell membrane function, deficits in energy metabolism associated with ubiquinone deficiency and reduction of small GTP-binding proteins involved in myocytes preservation (Nishimoto et al., 2003; Pierno et al., 1995). Guidelines from the American College of Cardiology/American Heart Association and the National Institute for Health and Care Excellence recommend moderate- to high-intensity statin therapy for primary prevention of CVD (Stone et al., 2014; National Institute for Health and Care Excellence, 2014). Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels are still a global and highly significant risk factor for cardiovascular disease (CVD). - exhibits biverticillate branching meaning that the conidiophore can branch and the metulae & phialides extend from these branches. Penicillium species are very important economically. Penicillium citrinum: Taxonomy navigation › Penicillium. Similar interactions between type I PKS and monofunctional proteins also occur in bacterial systems, for example, between multimodular and monofunctional proteins involved in mupirocin biosynthesis in Pseudomonas fluorescens.27. P. citrinum. During damp […] Put on the spot, I typed in, Blogger's text editor has at times refused to accept the symbol. A list of fungal reference text books I found useful in preparing this blog can be found further below in this sidebar. (Nikon). Compounds closely related are compactin (44) from Monascus ruber65 and pravastatin (45) from Penicillium citrinum.66, This class of compounds is known to inhibit cholesterol biosynthesis by inhibiting the rate- limiting step in cellular cholesterol biosynthesis, namely the conversion of hydroxymethylglutaryl-CoA (HMG-CoA) into mevalonate by HMG-CoA reductase. A specialized AT, encoded by lovD, transfers 46 from LDKS onto the C-10 hydroxyl of monacolin J (45).16 Tang and coworkers expressed lovD in Escherichia coli and showed that the recombinant protein will also transfer various acyl groups from CoA to the C-10 hydroxyl of 45 (Scheme 5).29. The side-chain is also composed of two acetate units.67. Transfer of the lovastatin diketide (46) from its PKS to monacolin-J (45) by lovD. The ITS regions and parts of the β-tubulin and calmodulin gene were sequenced and analysed. Indeed, the cardioprotective effects of red yeast were in some instances greater than lovastatin, implying that other monacolins, phytosterols, or yet to be identified active ingredients are also important. Scheme 5. A Clinical Guide and Laboratory Manual of Dermatophytes and Other Filamentous Fungi from Skin, Hair, and Nails. However, the role of these two enzymes in N-glycan processing is not established since they are both secreted enzymes with cleavable N-terminal signal sequences and a relatively acidic pH optimum of 5.0. Near the N-terminus is located the KS region, centering around the active site cysteine to which the acyl chain is attached prior to condensation with the malonyl extension unit on ACP-pantetheine-SH. These pyrones are related to the expected nonaketide, for example, the methylation has occurred at the correct position (i.e., after the third extension reaction), but it is evident that reductions – specifically enoyl reductions, and later keto reductions – have not occurred correctly and that chain extension has terminated prematurely (Scheme 4). service and if my profile appears there I am unaware of its origin. Penicillium citrinum ATCC ® 9849™ Designation: [11, CBS 342.61, IFO 6352, IMI 321326, IMI 61272, JCM 22607, NRRL 756] Application: Fungus resistance testing Fungus resistance testing automotive components Fungus resistance testing paint Typical "fingers" made up of the metulae and phialide structures from which chains of conidia extend. Of the approximately 150 recognized species, some are frequently implicated in the deterioration of food … Recently, LNKS has been subjected to remarkable dissection by the group of Tang. In 1976, Endo and coworkers isolated the first HMGR inhibitor, mevastatin (compactin) (Figure 12.3), from a culture of Penicillium citrinum[41]. In the case of tenellin biosynthesis (see Section 1.09.4), a similar pattern of sequence was observed in the tenellin biosynthetic gene cluster, that is, the ER domain of the PKS appeared defective and an ‘extra’ lovC-like ER gene was located nearby.28 Expression of the tenellin synthetase alone led to the production of several compounds with altered polyketide programing, in particular numerous methyl isomers were observed by LCMS as well as less-reduced and chain-shortened analogues. This species has been isolated from various substrates such as soil, (tropical) cereals, Sikorski, in Comprehensive Medicinal Chemistry II, 2007, The statin class was first identified in the early 1970s by investigators at Sankyo who discovered that the natural product, compactin (mevastatin 1), isolated from microbial fermentations of Penicillium citrinum in a search for new antimicrobial agents, potently inhibited HMG-CoA reductase and lowered serum cholesterol levels in animals.61 Compactin (Figure 7) also effectively lowered serum total cholesterol and LDLc in heterozygous FH patients. The characteristic color in this product is due to the presence of citrinin-producing Penicillium species, mainly Penicillium citreoviridae, Penicillium atrium, and Penicillium islandicum. Annette Herscovics, in Comprehensive Natural Products Chemistry, 1999. The combination of red yeast and olive oil polyphenol extract reduced LDL cholesterol in patients and lowering of total cholesterol, LDL, TG, and ApoB, with LDL reduced by 24% and oxidized LDL by ~20% [116]. Potential explanations include use as inhibitors of environmental competitors or enhancers of their own growth. The I… The central part of the colony is green due to the presence of conidia. No legislation is available regarding citrinin presence in foodstuffs. Weinfield, M, et al. Comparison of MTs responsible for the methylation of RNA, DNA, and protein substrate has identified a sequence motif thought to be part of the SAM-binding domain.73,74, The linear organization of active sites was observed in the amino acid sequence to be KS→AT→DH→MT→ER→KR→ACP. The biosynthesis of these compounds has been studied intensely – isotopic feeding experiments25 have shown that two polyketide chains are required: a nonaketide and a methylated diketide. Growth responses to different temperatures and water activity values for Penicillium citreoviride and Penicillium citrinum, two of the most common molds, were investigated. Proposed and observed products of LNKS. Later Raper and Alexander (1945) selected a strain of P. crysogenum, more efficient than P. notatum, in the production of penicillin. Terminal (leaf) node. Coexpression of the tenellin synthetase with the lovC homologue led to exclusive production of the correctly programed polyketide. A plausible reaction scheme for lovastatin (6) biosynthesis is shown in Scheme 8. Penicillium citrinum is a commonly occurring filamen-tous fungus with a worldwide distribution and it may well be one of the most commonly occurring eukaryotic life forms on earth (Pitt 1979). Discussion. In the 1970s the Japanese microbiologist Akira Endo discovered two compounds (ML-236A and B) derived from the fungus Penicillium citrinum.4,5 Endo reported that ML-236B at nanomolar concentrations inhibited the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR),6 the rate-limiting step in endogenous cholesterol biosynthesis. Nwokocha, in Pharmacognosy, 2017. Penicillium spp. Penicillium citrinum is already known for producing mycotoxin citrinin and cellulose digesting enzymes like cellulase and endoglucanase, as well as xylulase. Please do not ask to be added to my non-existent, Fun With Microbiology (What's Buggin' You? They have sufficient similarity to other eucaryotic enzymes to be classified as members of the class 1 α-1,2-mannosidases. The nature of advantage provided by the production of HMGR inhibitors by select fungi is not well understood. Its importance in the present context lies not so much in the production of a mycotoxin of particular human significance, but in its ubiquity, so that any toxins produced can be expected to be very widely distributed in food and feed supplies. Penicillium citrinum P. citrinum has been a well recognised species for most of this century. The incidence of rhabdomyolysis is approximately 1 per 10,000; however, fatalities have been reported (Graham et al., 2004). Penicillium is often referred as Deuteromycetes. The first citrinin producer described was Penicillium citrinum, although several species included in the genera Penicillium, Aspergillus, and Monascus have been reported to be able to produce this toxin. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. P. citrinum has been reported to be a human-opportunistic pathogen responsible for keratitis, cutaneous infections, and pneumonia (25 – 28). Conidiophores (stipes) seen from which extend the metulae and conidia producing phialides. Medically Important Fungi, 5th Edition–A Guide to Identification, Publisher: Elsevier Science Ltd; 2nd Revised edition (March 1987), Deanna A Sutton, B.S., MT, SM (ASCP), RM, SM (AAM), Annette W. Fothergill, M.A., M.B.A., MT (ASCP), CLS (NCA), Publisher: Lippincott Williams & Wilkins; 1 edition (Sep 26 1997), G.S. Dada Patil, ... Kalyani Kumbhare, in Innovative Approaches in Drug Discovery, 2017. Enzymes and Organic acids production- many Penicillium species are used in the production of organic acids such as citric acid, gluconic acid, tartaric acid and enzymes l… One encodes a protein with significant homology to HMGR while the other appears to be an efflux pump [55]. It has been reported in rice and corn flour. Bureau of Animal Industry Bulletin 118: 61 (1910) [MB#165293] During that same year researchers at Beecham Laboratories isolated mevastatin from Penicillium brevicompactum[42]. 2.1.1 CHARACTERISTICS AND IMPORTANCE OF MICROFUNGI 11 2.1.2 Aspergillus niger 12 2.1.2.1 Pathogenicity of Aspergillus niger 13 2.1.2.2 Industrial Uses 13 2.1.2.3 Other Uses 14 2.1.3 Penicillium citrinum 15 2.2 BIOMASS AND ITS POTENTIALS 15 2.3 STRUCTURE OF THE PLANT CELL WALL 16 2.4 CHEMICAL COMPOSITION OF LIGNOCELLULOSE 17 In order to confirm this, lovB was expressed in the heterologous fungal host Aspergillus nidulans.16 Surprisingly, the polyunsaturated compounds 43 and 44 were isolated. 1, 2, 3. The fact that ‘defective’ ER domains are not removed from the HR PKS where lovC-type proteins are used to achieve programed enoyl reductions may be significant. I've reluctantly added it but may regret it. Its importance in the present context lies not so much in the production of a mycotoxin of particular human significance, but in its ubiquity, so that any toxins produced can be expected to be very widely distributed in food and feed supplies. 10:1607-1618. Penicillium are cosmopolitan, predominant in regions of temperate climate. Although mevastatin was initially detected by its antifungal activity [57], the magnitude of this effect was not published. J.A. (1000X, LPCB, DMD-108) Penicillium citrinum- a little less congested in this photo. The association between lipid lowering and HMG-CoA reductase inhibition was later shown with lovastatin to be due to an upregulation of the LDLr and the resulting enhanced clearance from plasma of excess LDLc.34 The development of lovastatin was slowed by safety considerations surrounding compactin and the perceived underlying uncertainties associated with the potential consequences of long-term cholesterol biosynthesis inhibition. In the bacterial modular PKS systems there is usually a C-terminal thiolesterase (TE) domain involved in off-loading the product, either to another PKS or to solution.4 LNKS appears to possess a part of a nonribosomal peptide synthetase (NRPS) condensation (C) domain immediately downstream of the ACP, and this domain has been proposed to be involved in product release, presumably by either activating water as a nucleophile or the C-5 hydroxyl (rather than the nitrogen of an aminothiolester as activated by most NRPS C domains). Penicillia are of tremendous economic importance. The maximum cellulase activity was recorded in the range of pH- 5 to 6.5 and wheat bran (91 U/ml) and rice bran (81 U/ml) is the best raw substrate for the production of cellulase. Few reports are available about acute toxicity of citrinin. 7H 2 O, 0.05% KCl, FeSO 4 0.01 g, and Bacto-yeast extract 1 g, glucose 30 g, and adjusted to pH 6.5 in 1 L). Penicillium, genus of blue or green mold fungi (kingdom Fungi) that exists as asexual forms (anamorphs, or deuteromycetes ). The AT functional site with the GXSXG motif71 is identified in the position next to the KS site from its N-terminus. de Hoog, J. Guarro, J.Gené & M.J. Figueras, Centraalbureau voor Schimmelcultures/Universitat Rovira I Virgili, 2000, Publisher: American Society Microbiology; 2 edition (Jan 21 2002), Identifying Fungi – A Clinical Laboratory Handbook, Guy St-Germain, B.S.. Laboratoire de Santé Publique du Québec, Canada, Richard Summerbell, PH.D., Ontario Ministry of Health, Canada, Publisher: Star Publishing Company (Belmont, CA) (Jan 1 1996), Identification of Common Aspergillus Species, 1st edition, 2002, Agricultural Research Service, Southern Regional Research Center, ISBN 90-70351-46-3 Publisher: American Society Microbiology; 1 edition (Mar 1 2004). Mevinolin production was noted to reach its peak only after the dry weight of A. terreus had plateaued [53] and is dependent on the composition of the media [60]. (400X, LPCB, DMD-108). ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780121894108500201, URL: https://www.sciencedirect.com/science/article/pii/B9780128021040000159, URL: https://www.sciencedirect.com/science/article/pii/B9780080912837000758, URL: https://www.sciencedirect.com/science/article/pii/B9780123847300002342, URL: https://www.sciencedirect.com/science/article/pii/B9780128139394000310, URL: https://www.sciencedirect.com/science/article/pii/B9780124159228000124, URL: https://www.sciencedirect.com/science/article/pii/B9780128018149000027, URL: https://www.sciencedirect.com/science/article/pii/B9780080453828000174, URL: https://www.sciencedirect.com/science/article/pii/B008045044X001802, URL: https://www.sciencedirect.com/science/article/pii/B9780080912837000163, Bioactive Plant Molecules, Sources and Mechanism of Action in the Treatment of Cardiovascular Disease, Carbohydrates and Their Derivatives Including Tannins, Cellulose, and Related Lignings, Encyclopedia of Food Microbiology (Second Edition), Stone et al., 2014; National Institute for Health and Care Excellence, 2014, Nishimoto et al., 2003; Pierno et al., 1995, Natural Products Structural Diversity-I Secondary Metabolites: Organization and Biosynthesis, Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular, Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives, Biocatalysis and Agricultural Biotechnology. Colour variation due to maturing of colony but also a difference in my lighting for photography. As a first approach, modifications in lifestyle (i.e., exercise and diet) are usually a common indicator for controlling lipid levels in subjects with mild LDL-C elevations, but this recommendation is insufficient for patients needing stronger lipid reductions. However, 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors, widely known as statins, are by far the most commonly prescribed drug class worldwide to lower LDL-C levels. Although I strive to ensure all information is accurate some errors or differences of interpretation may occur. Citrinin is considered to be the major causal agent of the yellow rice disease described for a long time in Japan. Citrinin is produced by Penicillium citrinum and other Penicillium species. Both compounds are administered as inactive lactone prodrugs that must be metabolized in vivo to the corresponding open hydroxy-acid forms before HMG-CoA reductase inhibition can occur.54,62 Like compactin, lovastatin effectively lowered plasma LDLc in animals and produced profound reductions in serum LDLc in heterozygous FH patients. As noted above, since bacteria predominantly use the mevalonate-independent pathway, it is less likely that they will be significantly affected by the statins. Described in 1910, P. citrinum has been a well recognised species for most of this century. Scheme 4. Cheese production- many Penicillium species are used in the production of different kinds of cheese, e.g. J. Gil-Serna, ... B. Patiño, in Encyclopedia of Food Microbiology (Second Edition), 2014. The EF-hand consensus sequence includes an extra amino acid that may disrupt EF-hand helix formation, thereby eliminating its potential for Ca2+ binding.134 The Penicillium enzyme was inactivated by chemical modification of acidic residues with a water-soluble carbodiimide, and a specific aspartic acid residue (Asp375) was shown to be protected from this inactivation by the inhibitor 1-deoxymannojirimycin.135 A conclusive role of this residue in catalysis has not yet been established. Many other fine texts books and reference materials are available and the reader should decide what suits their own needs. Systematic review of 17 randomized controlled trials showed an increased risk of the development of diabetes. Statins are generally well tolerated but can produce a variety of skeletal muscle associated, dose-dependent adverse reactions, ranging from muscle pain to muscle cell damage and severe rhabdomyolysis (Thompson et al., 2003). Fine text books, peer reviewed scientific papers and other internet references are available for detailed descriptions and analysis. tem P. citrinum isolate demonstrated marked in vitro resis-tance to amphotericin B, itraconazole, fluconazole, and 5-flucytosine with MICs of .32 mg/ml (no zones of inhibition present) and a ketoconazole MIC of 1 mg/ml. Authors Fernando E Vega 1 , Francisco Posada, Stephen W Peterson, Thomas J Gianfagna, Fabio Chaves. The information and photographs presented here were compiled for my own entertainment and should not be used as an absolute reference for medical and/or diagnostic purposes. 4.42A, B). It is evident that the lovC protein must interact with LNKS intimately, drastically affecting programing by ensuring enoyl reduction at the correct positions and allowing complete chain extension. Thus the reason for fungal HMGR inhibitor production remains to be determined. 61 Compactin (Figure 7) also effectively lowered serum total cholesterol … Penicillium citrinum is currently utilized for production of the statin compactin, which is a precursor for the cholesterol lowering drug pravastatin (Endo et al. In November 1986, Merck submitted a New Drug Application (NDA) to the USFDA for lovastatin, which was approved in September 1987. In this scenario, Brazil is the largest producer of oranges; 34% of the global production, and exporter of concentrated orange juice; 76% of the juice consumed in the planet, summing up US$ 6.5 billion to Brazilian GDP. Many species of Penicillium adapt easily to indoor parameters and grow well on building materials. 1993. It is evident that the lovC protein must dock with the PKS in order to effect reduction, and the rump ER in the PKS sequence may act as a docking anchor; however, protein experiments have not yet been carried out to prove this hypothesis. Kingdom: FungiPhylum: AscomycotaClass: EuascomycetesOrder: EurotialesFamily: TrichomaceaeGenus: Penicillium In the case of lovastatin (19a) biosynthesis, the two PKS genes are lovB and lovF,26,16 encoding LNKS and LDKS, respectively. Apart from rice, the occurrence of this toxin has been reported in other cereals, fruits, cheese, and dried fruits, among others. Mevastatin was found to potently inhibit HMGR in vitro with a Ki of 1.4 nM [43], to inhibit cholesterol synthesis in tissue culture cells [44,45], and to reduce plasma cholesterol levels in dogs [46], monkeys [47], and humans [48]. Russell J. Cox, Thomas J. Simpson, in Comprehensive Natural Products II, 2010, Lovastatin (19a) (also known as mevinolin) is produced by Aspergillus terreus. 2.2. The importance of the 5'-base was reinforced by the finding that although P1 is essentially unspecific, ... Volbeda, A, et al. For ease of locating these books or further information about them, I have added links to Amazon. Gibberellins producing ability of this fungus and the discovery about the presence of GA5 will open new aspects of … Under damp conditions the wood of doors, windows and household furniture gets covered with a profuse growth of this fungus which spoils the wood. ), Streptococcus pneumoniae (Quellung Reaction), Unidentified Black Mould No. In this case clinicians can use several pharmacological alternates to achieve proper LDL-C goals according to the lipid fraction affected, such as fibrates, ezetimibe, bile acid sequestrants, and niacin. This occurred via an upregulation of fatty acid biosynthesis and an increase in the overall activity of the TCA cycle, as demonstrated by metabolomic analysis [Wu et al., 2015 ; Peng et al., 2015a ; Peng et al., 2015b ].