Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways

Abstract

Peroxisome proliferator-activated receptors (PPARs) control energy homeostasis. In this study, we showed that farnesol, a naturally occurring ligand of PPARs, could ameliorate metabolic diseases. Obese KK-Ay mice fed a high-fat diet (HFD) containing 0.5% farnesol showed significantly decreased serum glucose level, glucosuria incidence, and hepatic triglyceride contents. Farnesol-containing HFD upregulated the mRNA expressions of PPARα target genes involved in fatty acid oxidation in the liver. On the other hand, farnesol was not effective in upregulating the mRNA expressions of PPARγ target genes in white adipose tissues. Experiments using PPARα-deficient [(-/-)] mice revealed that the upregulation of fatty acid oxidation-related genes required PPARα function, but the suppression of hepatic triglyceride accumulation was partially PPARα-dependent. In hepatocytes isolated from the wild-type and PPARα (-/-) mice, farnesol suppressed triglyceride synthesis. In luciferase assay, farnesol activated both PPARα and the farnesoid X receptor (FXR) at similar concentrations. Moreover, farnesol increased the mRNA expression level of a small heterodimer partner known as one of the FXR target genes and decreased those of sterol regulatory element-binding protein-1c and fatty acid synthase in both the wild-type and PPARα (-/-) hepatocytes. These findings suggest that farnesol could improve metabolic abnormalities in mice via both PPARα-dependent and -independent pathways and that the activation of FXR by farnesol might contribute partially to the PPARα-independent hepatic triglyceride content-lowering effect. To our knowledge, this is the first study on the effect of the dual activators of PPARα and FXR on obesity-induced metabolic disorders.

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

“…The CAR-target gene CYP2B was also induced, although more strongly in rat than in mouse hepatocytes. Although CAR is suggested to influence hepatocellular lipid metabolism (Dong et al, 2009;Goto et al, 2011a), the panel of fatty acid-metabolizing enzymes altered by isoprenoids in this study did not appear to be strongly regulated through CAR activation.…”

“…†Statistically significant compared with DMSOtreated hepatocytes (P , 0.05). Takahashi et al, 2002;Goto et al, 2011a), which is suggested to partially account for some of these effects (Goto et al, 2011a). In the current study, many of the orthologs uniquely affected by SQ1 treatment were associated with fatty acid metabolism and are also transcriptional targets of PPARa.…”

“…SSIs also markedly reduce serum triglycerides through an LDL receptor-independent mechanism (Hiyoshi et al, 2001). The effect on triglyceride levels is thought to be mediated through farnesol and/or a farnesol metabolite (Hiyoshi et al, 2003), as farnesol treatment also decreased triglyceride biosynthesis and reduced hepatic steatosis, in part through PPARa activation (Duncan and Archer, 2008;Goto et al, 2011a). Elevated triglycerides are a known risk factor for CVD and are commonly associated with metabolic dyslipidemia (Eckel et al, 2005;Boullart et al, 2012).…”

“…Although the SSI lapaquistat (TAK-475) showed promising effects on serum lipid profiles in primates , its development was terminated during phase III clinical trials because of safety concerns and the lack of commercial viability at lower doses (Stein et al, 2011). Nonetheless, there is still significant interest in SSIs and the isoprenoid pathway with respect to hepatic lipid metabolism (Goto et al, 2011a;Nagashima et al, 2015) and as a potential therapeutic target for a variety of other conditions (Shang et al, 2014;Yang et al, 2014;Saito et al, 2015;Healey et al, 2016).…”

Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes

“…Nonsterol Isoprenoids Activate hCAR1 599 at ASPET Journals on May 12, 2018 dmd.aspetjournals.org Downloaded from Takahashi et al, 2002;Goto et al, 2011a). We previously reported that accumulation of isoprenoids in response to squalene synthase inhibition increased CYP2B1 expression in primary rat hepatocytes in a CAR-dependent manner (Kocarek et al, 1998;Kocarek and MercerHaines, 2002).…”