Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet

Toyoda, Yu; Takada, Tappei; Yamanashi, Yoshihide; Suzuki, Hiroshi

doi:10.1186/s12944-019-1179-0

Cited by 14 publications

(10 citation statements)

References 31 publications

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“…NPC1L1 is also expressed in the human liver and facilitates cholesterol reuptake from bile to hepatocytes[ 67 ]. Further experiments suggested that NPC1L1 may be associated with impaired VLDL-TG secretion and subsequent TG hepatic accumulation[ 68 ]. NPC1L1 inhibition by ezetimibe ameliorated hepatic steatosis in genetically engineered L1-Tg mice characterized by enhanced hepatic NPC1L1 expression[ 69 , 70 ].…”

Section: Ezetimibementioning

confidence: 99%

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Tzanaki¹,

Agouridis²,

Kostapanos³

2022

WJH

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Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

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Section: Ezetimibementioning

confidence: 99%

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Tzanaki¹,

Agouridis²,

Kostapanos³

2022

WJH

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“…NPC1L1, which reabsorbs cholesterol from bile and transports it to the liver, is expressed on the bile duct membrane and is an aggravating factor of NAFLD ( 120 ). NAFLD often exhibits oxidative stress, which leads to increased free-radical activity and lipid peroxidation by increasing reactive oxygen species (ROS).…”

Section: Bile Acid Metabolism In Nafldmentioning

confidence: 99%

Abnormal metabolic processes involved in the pathogenesis of non‑alcoholic fatty liver disease (Review)

Shao

Qin

et al. 2020

Exp Ther Med

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Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and can lead to liver cirrhosis or liver cancer in severe cases. In recent years, the incidence of NAFLD has increased substantially. The trend has continued to increase and has become a key point of concern for health systems. NAFLD is often associated with metabolic abnormalities caused by increased visceral obesity, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis and systemic microinflammation. Therefore, the pathophysiological mechanisms of NAFLD must be clarified to develop new drug treatment strategies. Recently, researchers have conducted numerous studies on the pathogenesis of NAFLD and have identified various important regulatory factors and potential molecular mechanisms, providing new targets and a theoretical basis for the treatment of NAFLD. However, the pathogenesis of NAFLD is extremely complex and involves the interrelationship and influence of multiple organs and systems. Therefore, the condition must be explored further. In the present review, the abnormal metabolic process, including glucose, lipid, amino acid, bile acid and iron metabolism are reviewed. It was concluded that NAFLD is associated with an imbalanced metabolic network that involves glucose, lipids, amino acids, bile acids and iron, and lipid metabolism is the core metabolic process. The current study aimed to provide evidence and hypotheses for research and clinical treatment of NAFLD.

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“…The liver is a critical organ for cholesterol synthesis and excretion to the intestinal lumen; however, around 95% of cholesterol excretion via hepatobiliary cholesterol excretion is absorbed by the intestine [ 9 ]. Previous studies have shown that routes for cholesterol secretion via hepatobiliary transport and trans-intestinal cholesterol secretion or excretion (TICE), which are direct transport pathways through intestinal enterocytes [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Soybean-Derived Peptides Attenuate Hyperlipidemia by Regulating Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

et al. 2021

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Increased triglyceride, cholesterol, and low-density lipoprotein (LDL) levels cause hyperlipidemia. Despite the availability of statin-based drugs to reduce LDL levels, additional effective treatments for reducing blood lipid concentrations are required. Herein, soybean hydrolysate prepared via peptic and tryptic hydrolysis promoted trans-intestinal cholesterol excretion (TICE) by increasing ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8 expression. The peptide sequence capable of promoting TICE was determined via HPLC and LC-MS/MS. Based on this, pure artificial peptides were synthesized, and the efficacy of the selected peptides was verified using cellular and hyperlipidemic mouse models. Soybean hydrolysates, including two bioactive peptides (ALEPDHRVESEGGL and SLVNNDDRDSYRLQSGDAL), promoted TICE via the expression of ABCG5 and ABCG8 in enterocytes. They downregulated expression of hepatic cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1 via expression of fibroblast growth factor 19 (FGF19) in a liver X receptor α (LXRa)-dependent pathway. Administration of bioactive peptides to hyperlipidemic mouse models by oral gavage reduced cholesterol levels in serum via upregulation of ABCG5 and ABCG8 expression in the proximal intestine and through fecal cholesterol excretion, upregulated FGF 15/19 expression, and suppressed hepatic bile acid synthesis. Oral administration of soybean-derived bioactive peptides elicited hypolipidemic effects by increasing TICE and decreasing hepatic cholesterol synthesis.

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Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet

Cited by 14 publications

References 31 publications

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Abnormal metabolic processes involved in the pathogenesis of non‑alcoholic fatty liver disease (Review)

Soybean-Derived Peptides Attenuate Hyperlipidemia by Regulating Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

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