• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • In recent large clinical studies AIM HIGH and


    In recent large clinical studies, AIM-HIGH and HPS2-THRIVE, the additional treatment of nicotinic 15 mg to statin-based LDL-C lowering therapy did not decrease the major vascular events on the patients who had atherosclerotic vascular diseases [43,44]. In the AIM-HIGH study, the secondary analysis showed a trend of decreased cardiovascular events in patients who have both high TG (≥198 mg/dL) and low HDL-C (<33 mg/dL) [45]. Therefore, nicotinic acid has a potential to treat such type of patients. To date, however, there are no reported GPR109A agonists that can induce clinically meaningful changes in LDL-C and HDL-C. Hence, whether GPR109A agonist could decrease the cardiovascular events is unclear. Meanwhile, considering our data and the result of GSK256073 in clinical study where about 36% plasma TG reduction was shown, GPR109A agonist could induce plasma TG lowering. Based on the preferable involvement of GPR109A on the glucose metabolism, GPR109A agonist may be a therapy for metabolic syndrome. The question has been raised as to why most GPR109A agonists failed to induce the plasma lipid changes seen with nicotinic acid in clinical studies. Potential reasons are that a rebound in baseline NEFA levels or tachyphylaxis were observed in those studies. Another possible reason is that nicotinic acid may have another molecular target. In this regard, in addition to Dgat2 reduction, nicotinic acid has also been reported to directly inhibit Dgat2 [38], and this might be a contributor to nicotinic acid efficacy. There is also the possibility that GPR109A is the main mediator of nicotinic acid TG-lowering, and it may simply be that the pharmacologic profile of the compound and its dosing regimen might be key factors for TG-lowering efficacy. There is a limitation in our study. The BAC clone used for creating Tg rats contains other genes such as Denr and Gpr81. Although we refered to the possible effects of these genes on the phenotype shown in Tg rats, we could not exclude the possibility that these genes affected the phenotype of Tg rats.
    Conflicts of interest
    Author contributions
    Introduction Multiple sclerosis (MS) affects an estimated 2.3 million people worldwide and carries a high socioeconomic burden (Browne et al., 2014; McKay et al., 2016). It is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. The inflammatory response and neurodegenerative mechanisms may lead to CNS injuries, culminating in neuronal damage and accumulation of clinical symptoms over time (McKay et al., 2016). The demyelination process in MS involves complex immunological mechanisms that rely upon interactions between the innate and the adaptive immune responses. The CNS inflammation observed in MS patients is associated with cytokines, such as IFN-γ and IL-17, produced by autoreactive Th1 and Th17 cells, respectively (Bettelli et al., 2006). The increased secretion of IFN-γ and IL-17 is dependent upon abnormal production of IL-12 and IL-23, respectively, by pro-inflammatory dendritic cells (DCs) (McGeachy et al., 2009). DCs are important to regulate the reactivation and differentiation of autoreactive effector and regulatory T-cells, determining whether the interaction will lead to autoimmunity or to tolerance (Bailey et al., 2007). In addition to T lymphocytes, B lymphocytes are also involved in the pathogenesis of MS. Besides autoantibody production, B-cells may act as antigen-presenting cells, produce pro-inflammatory cytokines that amplify T-cell responses, and are the major components of meningeal tertiary lymphoid structures that are associated with brain cortical demyelination and atrophy in MS patients (Michel et al., 2015). Dimethyl fumarate (DMF) was approved as a first-line oral therapy to treat relapsing forms of MS. Two pivotal phase III randomized, placebo-controlled trials, DEFINE and CONFIRM, demonstrated that DMF significantly reduced annualized relapse rates as well as the risk of relapse when compared to placebo (Gold et al., 2012; Fox et al., 2012). The phase III trials showed a reduction in the number of new or enlarging T2 lesions and gadolinium-enhancing lesions identified by brain magnetic resonance imaging (MRI). The DEFINE study demonstrated reduced risk of disability progression compared to placebo (Gold et al., 2012). Monomethyl fumarate (MMF), which results from the cleavage of DMF by intestinal esterases, is able to cross the blood-brain barrier, and can be detected in the CNS (Litjens et al., 2004). DMF is not detectable in plasma as the majority is metabolized into MMF and although a small fraction of DMF becomes conjugated to glutathione in plasma (Nelson et al., 1999).