Peroxisome Proliferator-Activated Receptor in Liver Disease

1. Introduction

Peroxisome proliferator-activated receptor, or PPAR, is a ligand-activated transcription factor belonging to the nuclear receptor superfamily that heterodimerizes with the retinoid X receptor and binds to peroxisome proliferator response elements (PPREs) in target gene promoters, affecting transcription of factors involved in lipid and glucose processing and inflammatory pathways. [1] This class of receptors is expressed extensively in the hepatocytes. Alpha agonists target lipid synthesis, gamma agonists influence glucose metabolism and insulin sensitivity, whereas delta agonists regulate the fatty acid cycle and fat metabolism.

In the liver, PPAR-alpha is the most abundant isoform and serves as the regulator of fatty acid catabolism. [2] Its activation upregulates genes encoding enzymes for mitochondrial, peroxisomal, and microsomal β-oxidation, including acyl-CoA oxidase and carnitine palmitoyltransferase 1 (CPT1),[3] thereby promoting fatty acid oxidation and reducing hepatic triglyceride accumulation. PPAR-alpha also represses sterol regulatory element-binding protein 1c (SREBP-1c), decreasing de novo lipogenesis and lipoprotein synthesis.

Beyond metabolic regulation, PPARα exerts anti-inflammatory effects by inhibiting nuclear factor kappa B (NF-κB) signaling and suppressing acute-phase response genes, including interleukin-6 receptor expression. [4] When PPAR-alpha expression is impaired, like in chronic alcohol exposure, fatty acid oxidation is compromised, leading to triglyceride accumulation, steatosis, and subsequent steatohepatitis. [3] Alpha receptors are thereby lipolytic and anti-inflammatory.

PPAR-gamma is predominantly expressed in white and brown adipose tissue, with lower expression in the liver, immune cells, and intestinal epithelium. [5] It is the master regulator of adipogenesis, promoting adipocyte differentiation, lipid storage, and insulin sensitization in peripheral tissues. In the liver, its activation can induce CD36-mediated fatty acid uptake and promote steatosis, but it also activates adipose triglyceride lipase and hormone-sensitive lipase, promoting triglyceride breakdown. [6]

Similar to PPAR-alpha, anti-inflammatory actions include inhibition of NF-κB,. In hepatic stellate cells, its activation induces a phenotypic switch from an activated, fibrogenic state to a quiescent state, providing an antifibrotic mechanism. [2]

PPAR-gamma also maintains intestinal barrier integrity and suppresses the growth of Enterobacteriaceae, a bacterial family implicated in the pathogenesis of MASLD. [2] Gamma receptors thereby exert net lipolytic, anti-inflammatory, and anti-fibrotic effects.

PPAR-beta/delta is particularly abundant in the liver, intestine, kidney, and skeletal muscle. [5] It regulates fatty acid oxidation, cholesterol metabolism, and energy expenditure. In the liver, its activation potentiates the fatty acid oxidation effects of PPARα and inactivates Kupffer cells, suppressing the release of inflammatory mediators. [5]

A key mechanism relevant to cholestatic liver disease is PPAR-delta-mediated upregulation of fibroblast growth factor 21 (FGF21), which signals through the JNK pathway to downregulate cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis. [7,8] This suppression of bile acid synthesis underlies the anticholestatic effects of PPARδ agonists in PBC.

2. Materials and Methods

This narrative review was conducted to comprehensively evaluate the role of PPAR agonists across the spectrum of liver diseases, including MASLD/MASH, ALD, PBC, PSC, IFALD, and ACLD. A systematic literature search was performed using PubMed, Embase, and the Cochrane Library databases from inception through May 2026.

The search strategy employed combinations of the following Medical Subject Headings (MeSH) terms and free-text keywords: “peroxisome proliferator-activated receptor,” “PPAR,” “PPARα,” “PPARγ,” “PPARδ,” “PPAR agonist,” “fibrate,” “fenofibrate,” “bezafibrate,” “pioglitazone,” “thiazolidinedione,” “elafibranor,” “seladelpar,” “lanifibranor,” “saroglitazar,” “SEFA-6179”, “metabolic dysfunction-associated steatotic liver disease,” “MASLD,” “metabolic dysfunction-associated steatohepatitis,” “MASH,” “nonalcoholic fatty liver disease,” “NAFLD,” “nonalcoholic steatohepatitis,” “NASH,” “alcohol-associated liver disease,” “alcoholic liver disease,” “primary biliary cholangitis,” “PBC,” “primary sclerosing cholangitis,” “PSC,” “intestinal failure-associated liver disease,” “IFALD,”.

Eligible studies included randomized controlled trials (RCTs), prospective and retrospective cohort studies, systematic reviews and meta-analyses, preclinical studies (in vitro and animal models), phase 1–3 clinical trials, and clinical practice guidelines from major hepatology societies (American Association for the Study of Liver Diseases [AASLD], European Association for the Study of the Liver [EASL]).

Exclusion criteria comprised case reports, non-English language publications without available translations, and studies evaluating PPAR agonists exclusively in non-hepatic conditions.

This review was not registered in PROSPERO, as it was designed as a narrative rather than a systematic review.

3. Results and Discussion

Since liver diseases involve overlapping metabolic, inflammatory, and fibrotic pathways, agents that activate multiple PPAR isoforms may offer broader therapeutic coverage than single-isoform agonists. Dual agonists (e.g., elafibranor [PPARα/δ], saroglitazar [PPARα/γ]) and pan-PPAR agonists (e.g., lanifibranor [PPARα/γ/δ], bezafibrate) aim to simultaneously address steatosis (via PPARα), insulin resistance and inflammation (via PPARγ), and bile acid/cholesterol metabolism (via PPARδ).

Table 1. Types of PPAR receptors and actions.

Feature	PPAR α	PPAR γ	PPAR β/δ
Primary hepatic role	Fatty acid β-oxidation	Insulin sensitization, anti-inflammation	Bile acid/cholesterol regulation
Key synthetic agonists	Fenofibrate, bezafibrate	Pioglitazone, rosiglitazone	Seladelpar
Dual/Pan agonists	Elafibranor (α/δ), saroglitazar (α/γ), lanifibranor (α/γ/δ)	-	-
Natural ligands	Omega-3 fatty acids, MCFAs	Docosahexaenoic acid	Oxidized phospholipids

Table 1. Types of PPAR receptors and actions.

Feature	PPAR α	PPAR γ	PPAR β/δ
Primary hepatic role	Fatty acid β-oxidation	Insulin sensitization, anti-inflammation	Bile acid/cholesterol regulation
Key synthetic agonists	Fenofibrate, bezafibrate	Pioglitazone, rosiglitazone	Seladelpar
Dual/Pan agonists	Elafibranor (α/δ), saroglitazar (α/γ), lanifibranor (α/γ/δ)	-	-
Natural ligands	Omega-3 fatty acids, MCFAs	Docosahexaenoic acid	Oxidized phospholipids

Table 2. Cholestatic effects of PPARα and PPARδ.

Feature	PPARα	PPARδ
Bile acid synthesis suppression	Represses CYP7A1 via LXRα-PPARα heterodimer on CYP7A1 promoter; also regulates CYP27A1, CYP8B1	Represses CYP7A1 via FGF21-JNK pathway, independent of FXR
Bile acid detoxification	Upregulates UGT1A1, UGT1A3, SULT2A1 (glucuronidation and sulfation)	Not established
Bile acid transport	Downregulates sinusoidal uptake (NTCP, OATP); upregulates canalicular efflux (MDR3/ABCB4), upregulates basolateral efflux (MRP3, MRP4)	Regulates ABCG5/ABCG8 cholesterol transport, increases bile flow
Phospholipid secretion	Upregulates MDR3 (biliary phospholipid secretion, protecting cholangiocytes)	Not established
Cell types affected in liver	Primarily hepatocytes	Hepatocytes, cholangiocytes, Kupffer cells, stellate cells
Anti-inflammatory mechanism	NF-κB inhibition; suppression of acute-phase response genes	Kupffer cell inactivation; macrophage polarization (PPARδ-dependent)
Antipruritic effect	Possible (fibrates show some benefit)	Statistically significant pruritus improvement (seladelpar in RESPONSE trial)

Table 2. Cholestatic effects of PPARα and PPARδ.

Feature	PPARα	PPARδ
Bile acid synthesis suppression	Represses CYP7A1 via LXRα-PPARα heterodimer on CYP7A1 promoter; also regulates CYP27A1, CYP8B1	Represses CYP7A1 via FGF21-JNK pathway, independent of FXR
Bile acid detoxification	Upregulates UGT1A1, UGT1A3, SULT2A1 (glucuronidation and sulfation)	Not established
Bile acid transport	Downregulates sinusoidal uptake (NTCP, OATP); upregulates canalicular efflux (MDR3/ABCB4), upregulates basolateral efflux (MRP3, MRP4)	Regulates ABCG5/ABCG8 cholesterol transport, increases bile flow
Phospholipid secretion	Upregulates MDR3 (biliary phospholipid secretion, protecting cholangiocytes)	Not established
Cell types affected in liver	Primarily hepatocytes	Hepatocytes, cholangiocytes, Kupffer cells, stellate cells
Anti-inflammatory mechanism	NF-κB inhibition; suppression of acute-phase response genes	Kupffer cell inactivation; macrophage polarization (PPARδ-dependent)
Antipruritic effect	Possible (fibrates show some benefit)	Statistically significant pruritus improvement (seladelpar in RESPONSE trial)

Available Agents

Mono-Receptor Agonists

• Fibrates- Fibrates are synthetic PPARα agonists used clinically for dyslipidemia. Fenofibrate selectively activates PPARα, increasing fatty acid β-oxidation, reducing apolipoprotein C-III expression, raising HDL cholesterol, and improving insulin sensitivity.

Notably, the fenofibrate has an off-label use for primary biliary cholangitis. Fenofibrate decreases 7α-hydroxy-4-cholesten-3-one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In a retrospective study of PBC and PSC patients with incomplete response to UDCA, combination fenofibrate treatment shifted bile acid metabolite profiles closer to those of healthy controls. [9] In a randomized clinical trial of 117 treatment-naive PBC patients, UDCA plus fenofibrate 200 mg achieved biochemical response (Barcelona criteria) in 81.4% vs. 64.3% with UDCA alone at 12 months (P = 0.048). [10]

2.

Thiazolidinediones- These are synthetic PPARγ agonists. Pioglitazone increases insulin sensitivity, decreases hepatic glucose production, reduces fasting glucose and HbA1c, and redistributes fat from visceral to subcutaneous depots. [6] It increases HDL and reduces triglyceride levels and had been used off label for the treatment of MASLD prior to approval of Resmetirom and Semaglutide.

3.

Seldelapar- Seladelpar is a selective PPARδ agonist that received FDA approval in August 2024 for PBC. [11]

Dual PPAR-Agonists

• Elafibranor- Elafibranor is a dual PPARα/δ agonist that received accelerated FDA approval in June 2024 for PBC after a successful ELATIVE phase 3 trial, in combination with UDCA in adults with inadequate response, or as monotherapy in patients unable to tolerate UDCA. [9] However, it did not meet its primary endpoint in the phase 3 RESOLVE-IT trial for MASH. [5] Both delta and alpha receptors have anti-cholestatic and anti-lipogenic effects, leading to trials in cholestatic and metabolic liver disease.
• Saroglitazar- A dual PPARα/γ (both metabolic) agonist approved in India for diabetic dyslipidemia and NASH but not FDA-approved. A phase 3 EPICS-III trial for PBC is ongoing (anti-cholestatic effects for alpha). [5,13]
• SEFA-6179- SEFA-6179 is a structurally engineered medium-chain fatty acid (MCFA) analogue that acts through PPARα, and PPARγ agonism. It is designed to resist β-oxidation, overcoming the rapid metabolism that limits natural MCFAs. Currently in preclinical and early phase II clinical development for IFALD. [14]

Pan-Receptor Agonists

• Bezafibrate- It activates all three PPAR isoforms and additionally agonizes the pregnane X receptor; it is approved in Europe and Japan but not in the United States for PBC. [15]
• Lanifibranor- a pan-PPAR agonist (PPARα/γ/δ) currently in phase 3 development for MASH. A phase 2 study in patients with type 2 diabetes and MASLD confirmed its safety profile, with mild gastrointestinal side effects and modest weight gain. [16]

Table 3. Liver Diseases targeted by PPAR Agonists.

Agent	Mechanism	MASLD/MASH	ALD	PBC	PSC	IFALD	ACLD
Fenofibrate	PPAR α	Reduces steatosis, TG	Preclinical	Off-label 2nd line with UDCA	Limited open-label data	—	—
Bezafibrate	Pan-PPAR	Improves dyslipidemia, IR	—	2nd line with UDCA; survival benefit	—	—	—
Pioglitazone	PPAR γ	Guideline-recommended; improves histology	—	—	—	—	—
Elafibranor	PPAR α/δ	Phase 3 failed (RESOLVE-IT)	Preclinical	FDA-approved (2024)	—	—	—
Seladelpar	PPAR δ	Phase 2b paused/resolved	—	FDA-approved (2024)	—	—	—
Lanifibranor	Pan-PPAR	Phase 3 ongoing (NATiV3)	—	—	—	—	Preclinical
Saroglitazar	PPAR α/γ	Early clinical data	—	Phase 3 ongoing (EPICS-III)	—	—	—
SEFA-6179	PPAR α/γ (MCFA)	—	—	—	—	Preclinical	—

Table 3. Liver Diseases targeted by PPAR Agonists.

Agent	Mechanism	MASLD/MASH	ALD	PBC	PSC	IFALD	ACLD
Fenofibrate	PPAR α	Reduces steatosis, TG	Preclinical	Off-label 2nd line with UDCA	Limited open-label data	—	—
Bezafibrate	Pan-PPAR	Improves dyslipidemia, IR	—	2nd line with UDCA; survival benefit	—	—	—
Pioglitazone	PPAR γ	Guideline-recommended; improves histology	—	—	—	—	—
Elafibranor	PPAR α/δ	Phase 3 failed (RESOLVE-IT)	Preclinical	FDA-approved (2024)	—	—	—
Seladelpar	PPAR δ	Phase 2b paused/resolved	—	FDA-approved (2024)	—	—	—
Lanifibranor	Pan-PPAR	Phase 3 ongoing (NATiV3)	—	—	—	—	Preclinical
Saroglitazar	PPAR α/γ	Early clinical data	—	Phase 3 ongoing (EPICS-III)	—	—	—
SEFA-6179	PPAR α/γ (MCFA)	—	—	—	—	Preclinical	—

• MASLD

Pioglitazone is the most extensively studied PPAR agonist in MASLD/MASH. In the phase 3 PIVENS trial, pioglitazone 30 mg for 96 weeks achieved NASH resolution in 47% vs. 21% with placebo in patients without diabetes, though the primary composite endpoint was not met at the prespecified significance threshold (P = 0.04 vs. required P = 0.025). A meta-analysis of five phase 2 randomized, placebo-controlled trials involving approximately 500 patients demonstrated that pioglitazone (30–45 mg daily for up to 24 months) reduced fibrosis severity and resolved MASH regardless of diabetes status, with a mean weight gain of 2.7 percentage points greater than placebo. [17]

In the phase 2b NATIVE trial, 247 patients with noncirrhotic, highly active MASH were randomized to lanifibranor 1200 mg, 800 mg, or placebo for 24 weeks. [19] The primary endpoint, a decrease of ≥2 points in the SAF-A score without worsening of fibrosis, was achieved in 55% of the 1200 mg group vs. 33% with placebo (P = 0.007). The phase 3 trial is currently underway, evaluating 72-week treatment with lanifibranor in adults with biopsy-confirmed MASH and F2–F3 fibrosis [18]

Saroglitazar (PPARα/γ) improved liver fat content on MRI-PDFF, insulin resistance, and atherogenic dyslipidemia in a small phase 2 trial in MASLD. [5] It is currently approved for MASLD treatment in India. Elafibranor (PPARα/δ) showed promise in the phase 2b GOLDEN-505 trial but failed to meet its primary endpoint in the phase 3 RESOLVE-IT trial in MASH, suggesting that the benefit of lanifibranor may derive primarily from its PPARγ agonist component. [5]

2.

Alcohol associated Liver Disease

Long-term alcohol consumption reduces fatty acid oxidation and increases triglyceride buildup by impairing PPARα function. Additionally, it interferes with PPARγ signaling, which leads to inflammation and the activation of stellate cells. Alcohol also weakens the intestinal barrier, which increases the translocation of bacterial products into the portal circulation, especially lipopolysaccharide, which activates Kupffer cells through NF-κB activation. [3] All evidence for PPAR agonists in ALD derives from animal models. No completed human clinical trials exist to date.

Seladelpar (MBX-8025) prevented and treated ethanol-induced liver disease in mice by reducing serum ALT, hepatic triglycerides, and inflammation while restoring gut barrier function and bile acid homeostasis. [19] Elafibranor significantly attenuated hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model, promoting lipolysis and β-oxidation via PPARα and restoring intestinal barrier function via PPARδ. [4]

3.

Primary Biliary Cholangitis

The AASLD states that fibrates can be considered as off-label alternatives for PBC patients with inadequate response to UDCA, though they are discouraged in decompensated cirrhosis. [20] In the BEZURSO trial, a prospective placebo-controlled RCT in France, bezafibrate improved liver biochemistries and liver stiffness in patients with an incomplete response to UDCA. [21] A large-scale retrospective analysis of 3,908 patients in Japan demonstrated that UDCA plus bezafibrate significantly reduced the risk of all-cause mortality or liver transplant Bezafibrate is not available in the United States. [22]

In the phase 3 ELATIVE trial, 161 patients with PBC and inadequate response to or intolerance of UDCA were randomized 2:1 to elafibranor 80 mg or placebo. [12] The primary endpoint biochemical response (ALP 1.67 × ULN, ≥15% ALP reduction, and normal total bilirubin) at 52 weeks was achieved in 51% vs. 4% (difference 47 percentage points, 95% CI 32–57; P 0.001). [18] ALP normalization occurred in 15% of elafibranor-treated patients vs. 0% with placebo (P = 0.002). [18] ALP reduction was rapid, with 59% meeting the primary endpoint by week 12. Pruritus scores on the WI-NRS did not differ significantly between groups (−1.93 vs. −1.15; P = 0.20), though secondary pruritus measures (PBC-40, 5-D itch scale) suggested possible improvement. Elafibranor also reduced triglycerides and VLDL cholesterol without adversely affecting LDL or HDL. Adverse events exceeding placebo included abdominal pain, diarrhea, nausea, and vomiting. [18] Elafibranor received accelerated FDA approval in June 2024. [12]

In the phase 3 RESPONSE trial, 193 patients with PBC were randomized to seladelpar 10 mg or placebo. [32] Biochemical response at 12 months was 61.7% vs. 20% (difference 41.7 percentage points, 95% CI 27.7–53.4; P 0.001), and ALP normalization occurred in 25% vs. 0% (P 0.001). [20,32] In a key secondary analysis of patients with moderate-to-severe pruritus, seladelpar significantly reduced pruritus NRS scores compared with placebo (−3.2 vs. −1.7; P = 0.005). [23] In the ENHANCE phase 3 trial (terminated early due to an erroneous safety signal in a concurrent MASH trial), seladelpar 10 mg achieved a biochemical response in 78.2% vs. 12.5% with placebo at 3 months (P=0.0001), with significant ALP normalization (27.3% vs. 0%) and improvement in pruritus. [24] No serious treatment-related adverse events were reported. [19] Seladelpar received FDA approval in August 2024.

4.

PSC- Unlike PBC, no pharmacotherapy has demonstrated efficacy in altering the natural history of PSC, and liver transplantation remains the only definitive treatment for advanced disease.

Evidence for the use of PPAR agonists in PSC is extremely limited. An open-label study demonstrated that fenofibrate 160 mg/day for 6 months significantly decreased serum ALP and ALT in patients with PSC. In the FITCH trial, bezafibrate improved cholestatic pruritus in a mixed cohort that included 46 patients with PSC. [25]

Several PPAR agonists are being evaluated in clinical trials for PSC, though the evidence base remains far behind that of PBC.

5.

IFALD- IFALD is a complication of long-term parenteral nutrition (PN), affecting 20–30% of patients with intestinal failure. It is particularly common in preterm neonates due to hepatic immaturity, susceptibility to proinflammatory lipids from PN, bacterial translocation across a disrupted intestinal epithelium, and sepsis. In adults, PN-associated hepatic lipogenesis causes steatosis.

SEFA-6179 is a structurally engineered MCFA analogue designed to resist β-oxidation, overcoming the rapid metabolism that limits natural MCFAs

EFA-6179 is a structurally engineered MCFA analogue designed to resist β-oxidation, overcoming the rapid metabolism that limits natural MCFAs. It acts through triple receptor agonism: GPR84, PPARα, and PPARγ.

Table 4. Class-wide adverse effects table.

Agent	Key Adverse Effects
Fenofibrate	Reversible creatinine elevation: FDA-contraindicated in PBC (used off-label)
Bezafibrate	Generally, well tolerated
Pioglitazone	Weight gain, edema, fractures, CHF exacerbation, bladder cancer risk
Elafibranor	Abdominal pain, diarrhea, nause
Seladelpar	Pruritus improvement: interface hepatitis signal (resolved)
Lanifibranor	Weight gain, peripheral edema
Saroglitazar	No significant weight gain
SEFA-6179	Preclinical only

Table 4. Class-wide adverse effects table.

Agent	Key Adverse Effects
Fenofibrate	Reversible creatinine elevation: FDA-contraindicated in PBC (used off-label)
Bezafibrate	Generally, well tolerated
Pioglitazone	Weight gain, edema, fractures, CHF exacerbation, bladder cancer risk
Elafibranor	Abdominal pain, diarrhea, nause
Seladelpar	Pruritus improvement: interface hepatitis signal (resolved)
Lanifibranor	Weight gain, peripheral edema
Saroglitazar	No significant weight gain
SEFA-6179	Preclinical only

5. Conclusions

PPAR agonists have moved from preclinical promise to FDA-approved therapies in PBC and remain in active phase 3 development for MASH, but are still in preclinical or early-phase stages for the rest (ALD, PSC, IFALD, ACLD). In PBC, both elafibranor and seladelpar received accelerated FDA approval based on biochemical response rather than transplant-free survival or mortality. Lanifibranor has demonstrated histological improvement (MASH resolution, fibrosis regression), with its superiority over elafibranor in MASH most likely, in our view, attributable to its PPARγ component. The evolution from single-isoform to pan-PPAR agonism reflects an overlapping mechanism in liver diseases.