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The farnesoid X receptor (FXR)
Bile acids are now believed to play a crucial role in regulating liver and metabolic homeostasis. Their
action is mediated through nuclear hormone receptors such as FXR and TGR5. Signalling through
these nuclear receptors modulates triglyceride, glucose and cholesterol homeostasis, in addition to bile
acid synthesis [28]. FXR is a member of the nuclear hormone receptor superfamily, which function as
ligand-activated transcription factors upon binding of bile acids or synthetic ligands. FXR activation
has a wide range of metabolic effects (Fig. 2). It improves both glucose metabolism (by inhibiting
gluconeogenesis and glycogenolysis in the liver) and peripheral IS (in the muscle and adipose tissue).
It also reduces lipogenesis by inhibiting SREBP1c and enhancing β-fatty acid oxidation. FXR-null
mice develop steatosis, but also hepatic inflammation, liver cell injury and HCC that is reminiscent
of human NASH. Interestingly, FXR activation has anti-inflammatory actions, partly explained by
inhibition of NF-kB activation and partly by immune modulation. Since FXR agonists protect against
liver inflammation and fibrosis in the methionine-choline deficient model of NASH, interest in this class
of agents as a treatment of human NASH has been growing.
Several potent, synthetic FXR agonists are available. Obeticholic acid (OCA), a derivative of
chenodeoxycholic acid, is a selective FXR agonist which acts as a potent metabolic regulator with
antiinflammatory, immunomodulatory and antifibrotic properties [29]. A small randomized trial in
T2DM patients with NAFLD showed an improvement in IS, a modest but dose-related weight loss
of potential clinical relevance, a reduction in ALT levels at the lower, 25 mg dose and divergent effects
on the lipid profile with a decrease in triglyceride levels and an increase in LDL cholesterol levels [30].
Recently the NASH CRN reported the results of a large phase 2b study comparing 25 mg of OCA vs.
placebo over 72 weeks of therapy [31].The primary endpoint was improvement in histology, as measured
by a two-point reduction in a composite activity histological score without worsening of fibrosis. The
therapeutic phase of the trial was stopped early partly because a pre-planned interim analysis showed
that 45% (50 of 110) and 21% (23 of 109) of the OCA and placebo patients, respectively, reached the
primary endpoint (relative risk 1.9, 95% CI 1.3–2.8). In terms of fibrosis score, 35% (36 of 102) and
19% (19 of 98) of the OCA and placebo patients, respectively, regressed by one stage or more. These
are very encouraging data that certainly deserve confirmation in larger trials. The most concerning side
effects were pruritus and an increase in LDL cholesterol. Studies are underway to fully understand the
lipid changes in order to determine whether they are associated with increased cardiovascular risk or
not.
Peroxisome proliferator and activator dual agonists
Peroxisome proliferator-activated receptor (PPAR)-δ, a ubiquitously expressed member of the lipid-
activated nuclear receptor superfamily, has emerged as a key metabolic regulator (Fig. 3) [32, 33].
PPAR-δ activation results in an increase in hepatic fatty acid β-oxidation, inhibition of hepatic lipogenesis
(by inhibiting maturation and translocation of SREBP1c), reduction of hepatic glucose production
(mediated through activation of AMPK), and improvement in hepatic inflammation (mediated through
inhibition of STAT3). PPAR-δ exerts hepatoprotective effects, in particular against lipotoxicity, an
action that is mediated through a reduction in JNK phosphorylation and in the expression of multiple
inflammatory cytokines [34], as well as through modulation of macrophage inflammatory activity [35].
Recently, antifibrotic effects of PPAR-δ agonists have also been described in models of liver injury [35].
Therefore, a strong rationale for PPAR-δ agonists as pharmacological agents in NASH exists.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 73
Bile acids are now believed to play a crucial role in regulating liver and metabolic homeostasis. Their
action is mediated through nuclear hormone receptors such as FXR and TGR5. Signalling through
these nuclear receptors modulates triglyceride, glucose and cholesterol homeostasis, in addition to bile
acid synthesis [28]. FXR is a member of the nuclear hormone receptor superfamily, which function as
ligand-activated transcription factors upon binding of bile acids or synthetic ligands. FXR activation
has a wide range of metabolic effects (Fig. 2). It improves both glucose metabolism (by inhibiting
gluconeogenesis and glycogenolysis in the liver) and peripheral IS (in the muscle and adipose tissue).
It also reduces lipogenesis by inhibiting SREBP1c and enhancing β-fatty acid oxidation. FXR-null
mice develop steatosis, but also hepatic inflammation, liver cell injury and HCC that is reminiscent
of human NASH. Interestingly, FXR activation has anti-inflammatory actions, partly explained by
inhibition of NF-kB activation and partly by immune modulation. Since FXR agonists protect against
liver inflammation and fibrosis in the methionine-choline deficient model of NASH, interest in this class
of agents as a treatment of human NASH has been growing.
Several potent, synthetic FXR agonists are available. Obeticholic acid (OCA), a derivative of
chenodeoxycholic acid, is a selective FXR agonist which acts as a potent metabolic regulator with
antiinflammatory, immunomodulatory and antifibrotic properties [29]. A small randomized trial in
T2DM patients with NAFLD showed an improvement in IS, a modest but dose-related weight loss
of potential clinical relevance, a reduction in ALT levels at the lower, 25 mg dose and divergent effects
on the lipid profile with a decrease in triglyceride levels and an increase in LDL cholesterol levels [30].
Recently the NASH CRN reported the results of a large phase 2b study comparing 25 mg of OCA vs.
placebo over 72 weeks of therapy [31].The primary endpoint was improvement in histology, as measured
by a two-point reduction in a composite activity histological score without worsening of fibrosis. The
therapeutic phase of the trial was stopped early partly because a pre-planned interim analysis showed
that 45% (50 of 110) and 21% (23 of 109) of the OCA and placebo patients, respectively, reached the
primary endpoint (relative risk 1.9, 95% CI 1.3–2.8). In terms of fibrosis score, 35% (36 of 102) and
19% (19 of 98) of the OCA and placebo patients, respectively, regressed by one stage or more. These
are very encouraging data that certainly deserve confirmation in larger trials. The most concerning side
effects were pruritus and an increase in LDL cholesterol. Studies are underway to fully understand the
lipid changes in order to determine whether they are associated with increased cardiovascular risk or
not.
Peroxisome proliferator and activator dual agonists
Peroxisome proliferator-activated receptor (PPAR)-δ, a ubiquitously expressed member of the lipid-
activated nuclear receptor superfamily, has emerged as a key metabolic regulator (Fig. 3) [32, 33].
PPAR-δ activation results in an increase in hepatic fatty acid β-oxidation, inhibition of hepatic lipogenesis
(by inhibiting maturation and translocation of SREBP1c), reduction of hepatic glucose production
(mediated through activation of AMPK), and improvement in hepatic inflammation (mediated through
inhibition of STAT3). PPAR-δ exerts hepatoprotective effects, in particular against lipotoxicity, an
action that is mediated through a reduction in JNK phosphorylation and in the expression of multiple
inflammatory cytokines [34], as well as through modulation of macrophage inflammatory activity [35].
Recently, antifibrotic effects of PPAR-δ agonists have also been described in models of liver injury [35].
Therefore, a strong rationale for PPAR-δ agonists as pharmacological agents in NASH exists.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 73
