Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

Connelly, Margery A.; Rivera, Jonathan Velez; Guyton, John R.; Siddiqui, Mohammad Shadab; Sanyal, Arun J.

doi:10.1111/apt.15935

Cited by 9 publications

(5 citation statements)

References 170 publications

(357 reference statements)

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“…However, its clinical applications may be limited by various side effects, including fluid retention and weight gain. [ 34 ] We found that pharmacologic inhibition of the expression of ACSL4 by administering abemaciclib at 30 mg/kg per day significantly suppressed body weights and improved NASH‐associated pathological features, including hepatic steatosis and fibrosis. In 2017, Abemaciclib was approved by the United States Food and Drug Administration (FDA) to treat hormone receptor‐positive and HER2‐negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice

et al. 2021

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Background and Aims Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. Approach and Results In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β‐oxidation of fatty acids and to minimize lipid accumulation by up‐regulating peroxisome proliferator‐activated receptor coactivator‐1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. Conclusions Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.

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Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice

et al. 2021

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“…FXR regulates bile acid synthesis by suppressing key enzymes in the biosynthetic pathway [14]. A number of therapies are under investigation for the treatment of NAFLD and NASH [5,15,16], however, no pharmacological agent is currently approved. FXR agonists are in clinical development for the treatment of NASH as well as other chronic liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 Study of EDP-305, a Novel Once-Daily Oral Farnesoid X Receptor Agonist, in Healthy Subjects and Those with Presumptive Nonalcoholic Fatty Liver Disease

Ahmad¹,

Sanderson²,

Dickerson³

et al. 2021

IJG

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Introduction: EDP-305 is a farnesoid X Receptor (FXR) agonist that selectively activates FXR and is currently under investigation for with the treatment of nonalcoholic steatohepatitis (NASH). The primary objective was to assess the safety of EDP-305 in healthy subjects and subjects with presumptive NAFLD. Methods: In this placebo-controlled doubleblind Phase 1 study, healthy subjects (aged 20-55 years) were randomized to single or multiple oral doses of once daily EDP-305 or placebo and subjects with presumptive NAFLD (aged 25-52 years) were randomized to multiple oral doses of once daily EDP-305 or placebo for 14 days. Six cohorts received EDP-305 1 mg, 5 mg, 10 mg, 20 mg, 40 mg or 80 mg in the SAD phase including a food effect cohort that received EDP-305 10 mg. In the MAD phase, 12 cohorts received EDP-305 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg or 20 mg (six cohorts in healthy subjects and six in presumptive NAFLD). Results: In the SAD phase, 38 subjects received EDP-305 and 12 subjects received placebo, and in the MAD phase, 72 subjects received EDP-305 and 24 subjects received placebo. No serious adverse events were reported, and the most common treatment-emergent adverse events (TEAEs) in EDP-305 treated subjects were constipation, headache, and pruritus. The majority of TEAEs were mild to moderate in severity. EDP-305 exposure increased with single and multiple doses in both healthy subjects and those with presumptive NAFLD. EDP-305 exposure was approximately 3-fold higher in fed vs. fasted subjects. Strong FXR target engagement was demonstrated in both healthy and presumptive NAFLD subjects in the MAD phase with FGF19 increases and C4 reductions compared with placebo. Conclusion: EDP-305 was well tolerated, with pruritus the most common treatmentemergent adverse event at EDP-305 doses ≥10 mg and with minimal effects on lipids. Dose proportional PK support once daily dosing. Significant elevations of FGF19 and diminutions in C4 demonstrated potent engagement of the FXR receptor at doses that neither elicit adverse effects on lipids nor result in pruritus. These results supported further evaluation of EDP-305 in patients with NASH.

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“…On the other hand, there are novel therapies under investigation (20)(21)(22)(23) alone or in combination (24,25): Glucagon-Like Peptide 1(GLP1) Agonist, Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, Peroxisome Proliferator-Activated-Receptor (PPAR) agonist, Caspase inhibitors, Acetyl-CoA inhibitors, Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors, and Farnesoid X Receptor (FXR) agonists. Some of these therapies increase serum lipids and the combination of statins with them will mitigate this effect (26). The results of phase 3 trials with these drugs will shed light on future treatment of NASH/NAFLD.…”

Section: Pharmacotherapy In Nash/nafldmentioning

confidence: 99%

Statins in Non-alcoholic Steatohepatitis

Torres-Peña

Martín-Piedra

Fuentes-Jiménez

2021

Front. Cardiovasc. Med.

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Non-alcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease. The range is extensive, including hepatocellular carcinoma, cirrhosis, fibrosis, fatty liver, and non-alcoholic steatohepatitis (NASH). NASH is a condition related to obesity, overweight, metabolic syndrome, diabetes, and dyslipidemia. It is a dynamic condition that can regress to isolated steatosis or progress to fibrosis and cirrhosis. Statins exert anti-inflammatory, proapoptotic, and antifibrotic effects. It has been proposed that these drugs could have a relevant role in NASH. In this review, we provide an overview of current evidence, from mechanisms of statins involved in the modulation of NASH to human trials about the use of statins to treat or attenuate NASH.

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Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

Cited by 9 publications

References 170 publications

Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice

Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice

Phase 1 Study of EDP-305, a Novel Once-Daily Oral Farnesoid X Receptor Agonist, in Healthy Subjects and Those with Presumptive Nonalcoholic Fatty Liver Disease

Statins in Non-alcoholic Steatohepatitis

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