Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway

Nakamuta, Makoto; Fujino, Tatsuya; Yada, Ryoko; Yasutake, Kaori; Yoshimoto, Tsuyoshi; Harada, Naohiko; Yada, Masayoshi; Higuchi, Nobito; Kato, Masaki; Kohjima, Motoyuki; Taketomi, Akinobu; Maehara, Yoshihiko; Nishinakagawa, Takuya; Machida, Kazuyuki; Matsunaga, Kazuhisa; Nakashima, Mitsuyoshi; Kotoh, Kazuhiro; Enjoji, Munechika

doi:10.5414/cpp48022

Cited by 20 publications

(16 citation statements)

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“…In hepatocytes, LXRα regulates cholesterol and fatty acid metabolism, and its endogenous agonistic ligands are oxysterols [7-10]. We have previously examined expression of lipid metabolism-associated genes in NAFLD liver [11-18]. As a result, despite cholesterol overload in hepatocytes, cholesterol synthesis is activated in the NAFLD liver, meaning cholesterol metabolism is dysregulated in NAFLD.…”

Section: Discussionmentioning

confidence: 99%

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

et al. 2010

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BackgroundWe recently examined the distribution of abdominal fat, dietary intake and biochemical data in patients with nonalcoholic fatty liver disease (NAFLD) and found that non-obese NAFLD patients did not necessarily exhibit insulin resistance and/or dysregulated secretion of adipocytokines. However, dietary cholesterol intake was superabundant in non-obese patients compared with obese patients, although total energy and carbohydrate intake was not excessive. Therefore, excess cholesterol intake appears to be one of the main factors associated with NAFLD development and liver injury.MethodsWe reviewed a year of follow-up data of non-obese NAFLD patients treated with Niemann-Pick C1 like 1 inhibitor ezetimibe to evaluate its therapeutic effect on clinical parameters related to NAFLD. Without any dietary or exercise modification, 10 mg/day of ezetimibe was given to 8 patients. In 4 of 8 patients, ezetimibe was administered initially. In the remaining 4 patients, medication was switched from ursodeoxycholic acid to ezetimibe.ResultsIn each patient, body mass index was maintained under 25 kg/m2 during the observation period. Serum ALT levels significantly decreased within 6 months and in 4 patients levels reached the normal range (<30 U/L), which was accompanied with at least a 10% decrease in serum total cholesterol and LDL-cholesterol. However, ultrasonographic findings of fatty liver did not show obvious improvement for a year.ConclusionWe conclude that the cholesterol absorption inhibitor ezetimibe can suppress hepatic injury in non-obese patients with NAFLD and that ezetimibe may offer a novel treatment for NAFLD.

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Section: Discussionmentioning

confidence: 99%

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

et al. 2010

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“…It is necessary to test new drugs that have been able to stop steatosis. Among the new drugs being tested, we emphasize the Allopurinol [89], omega-3 fatty acids [90], bezafibrate [91], the combination of ezetimibe/simvastatin [92], SRT1720 (SIRT1 activator) [93], Viusid (nutritional supplement) [94], Pan-caspase [95], bicyclol [96] and Losartan [97] among others. It has been observed that these drugs may be promising, as they decrease injuries NAFLD.…”

Section: Future Therapeutic Targetsmentioning

confidence: 99%

Inflammatory Mediators of Hepatic Steatosis

Hijona

Arenas

et al. 2010

Mediators of Inflammation

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Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications.

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“…Ghonem and colleagues observed that fenofibrate transactivates ABCB4 gene transcription through the binding of PPARα to three novel and functionally critical PPREs in the ABCB4 promoter with concomitant increase in the excretion of phosphatidylcholine from hepatocytes into bile canaliculi, thereby providing a functional correlate [34]. In another study, bezafibrate promotes the secretion of phospholipids into bile via triggering the PPARα/MDR3 signaling pathway in cholestatic patients undergoing percutaneous transhepatic biliary drainage [35]. In addition, studies from our own and other groups have found that ABCA1 and ABCG1 play important roles in mediating the active efflux of phospholipids to apoA-I and high-density lipoprotein (HDL), respectively [64,65].…”

Section: Pparα Regulates Phospholipid Metabolismmentioning

confidence: 92%

“…Recently, growing evidence has shown that PPARα is implicated in metabolic processes of multiple lipids, including cholesterol, triglyceride, phospholipid, bile acids, and fatty acids (Table 1). NPC1L1 Upregulation, downregulation [22][23][24] ABCG5, ABCG8 Upregulation [25] Triglyceride metabolism LPL Upregulation [26][27][28] ApoA-V Upregulation [29,30] Angptl4 Upregulation [31,32] ApoC-III Downregulation [33] Phospholipid metabolism ABCB4 Upregulation [34,35] ABCA1 Upregulation [36] Bile acid metabolism…”

Section: Pparα and Lipid Metabolismmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis

Zheng

Tang

2015

Advances in Clinical Chemistry

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Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway

Cited by 20 publications

References 0 publications

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

Inflammatory Mediators of Hepatic Steatosis

Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis

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