Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging

Kim, Sang Woo; Lee, Bonggi; An, Hye Jin; Kim, Dae Hyun; Park, Kyung Chul; Noh, Sang-Gyun; Chung, Ki Wung; Lee, Eun Kyeong; Kim, Kyung Mok; Kim, Do Hyun; Kim, Su Jeong; Chun, Pusoon; Lee, Ho Jeong; Moon, Hyung Ryong; Chung, Hae Young

doi:10.18632/oncotarget.17695

Cited by 19 publications

(13 citation statements)

References 22 publications

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“…Excessive intake of dietary lipids was shown to decrease hepatic PPAR␣ and PGC-1␣ expression with a reduced numerical density of hepatic mitochondria (65). A number of PPAR␣ agonists have been shown to enhance hepatic mitochondrial biogenesis and increase fatty acid ␤-oxidation in diet-induced obese mice (66,67). As an upstream regulator of AKT, PPAR␣, and PGC-1␣, PRMT5 might be a valuable target to treat fatty liver via multiple mechanisms or may be even more broadly applied to other diseases that are associated with mitochondrial dysfunction.…”

Section: Prmt5 Inhibition Enhances Mitochondrial Biogenesismentioning

confidence: 99%

Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Huang

Liu

Zhang

et al. 2018

Journal of Biological Chemistry

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Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat-induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral short hairpin RNA-mediated reduction of PRMT5 significantly decreased phosphatidylinositol 3-kinase/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation but boosted the expression of peroxisome proliferator-activated receptor α (PPARα) and PGC-1α with a concomitant increase in mitochondrial biogenesis. Moreover, by overexpressing an exogenous WT or enzyme-dead mutant PRMT5 or by inhibiting PRMT5 enzymatic activity with a small-molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARα and PGC-1α expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for the treatment of fatty liver.

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Section: Prmt5 Inhibition Enhances Mitochondrial Biogenesismentioning

confidence: 99%

Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Huang

Liu

Zhang

et al. 2018

Journal of Biological Chemistry

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“…25,26 Moreover, it is an appropriate tool of investigation to determine the alteration of fatty acid oxidation [27][28][29] and mitochondrial dysfunction. As known, HepG2 cells represent, among hepatoma cell lines, the most common in vitro model to evaluate DILI and drug metabolism with high similarity to primary human hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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Sodium valproate (VPA), an antiepileptic drug, may cause dose-and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations.Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment. K E Y W O R D Santiepileptic drug, hepatotoxicity, lipid metabolism, mitochondrial dysfunction, oxidative stress, shortchain fatty acid | 677 PIROZZI et al. | 679 PIROZZI et al. incubated with tert-Butyl hydroperoxide (100 µM) plus H 2 O 2 for 3 hours. The fluorescence measurements were performed with aHTS-7000 Plus plate reader spectrofluorometer (Perkin Elmer, Wellesley, MA, USA) at 485 nm for excitation and 525 nm for emission wavelengths. ROS were quantified as percentage vs control unstimulated cells.

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“…Accordingly, a similar dose of elafibranor has previously been shown to reduce steatohepatitis and liver fibrosis following 7 weeks of treatment to MCD diet-fed db/db mice [ 67 ], and other PPAR agonists can reduce fibrotic NASH when administered for 10–12 weeks in mouse and rat CDAA models [ 23 , 71 ]. Previous studies have reported anti-steatotic, anti-inflammatory, and anti-fibrotic effects of PPAR subtype-selective agonists for the α [ 72 , 73 ], δ [ 74 , 75 ], and γ [ 76 , 77 ] isoforms, making it conceivable that elafibranor, a dual PPAR-α/δ agonist, exerts its therapeutic effects through various PPAR-associated signaling mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

Tølbøl¹,

Stierstorfer²,

Rippmann³

et al. 2018

Dig Dis Sci

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Background There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease. Methods Here, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient l -amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. Results The CDAA diet led to marked hepatomegaly and fibrosis already after 4 weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores. Conclusion CDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.

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Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging

Cited by 19 publications

References 22 publications

Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

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