Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis

Ling, Chen-Jie; Xu, Jia‐Ying; Li, Yunhong; Tong, Xiaojiao; Yang, Huanhuan; Yang, Jing; Yuan, Linxi; Qin, Li–Qiang

doi:10.1039/c9fo01616c

Cited by 22 publications

(18 citation statements)

References 39 publications

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“…As CYP7A1 is a rate-limiting step for bile acid synthesis and CYP8B1 determines the synthetic flow of cholesterol in hepatocytes, regulating the expression levels of these proteins altered the amount and profile of biosynthetic cholesterol [ 8 ]. The results of the current study are consistent with reports indicating that hepatic CYP7A1 and CYP8B1 expression are lowered in diet-induced hyperlipidemia models and that FGF15/19 suppressed expression of both these genes [ 44 , 45 ]. Recently, the pharmacological induction of distal intestinal FGF15/19 led to hepatic bile acid metabolism and further enhanced fecal cholesterol excretion in combination with ezetimibe, a TICE inducer [ 10 ].…”

Section: Discussionsupporting

confidence: 92%

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Lee

Youn

2020

Nutrients

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Hyperlipidemia, a syndrome characterized by an abnormal elevation of blood lipids, causes chronic lethal metabolic disorders. Although statins are regularly prescribed to patients, an alternative to treat the burden of excessive lipids is required for cholesterol control. In this study, it was found that the treatment of casein hydrolyzed by pepsin and trypsin induced trans-intestinal cholesterol excretion (TICE) through ATP-binding cassette subfamily G members 5 (ABCG5) expression. Next, we analyzed sequences of the peptides responsible for TICE induction, synthesized artificial peptides based on the sequences, and the hypolipidemic effects of the peptide treatments were assessed in both in vitro and in vivo models. We determined that two bioactive peptides contained in casein hydrolysates (SQSKVLPVPQK and HPHPHLSF) induced TICE through the expression of ABCG5 in enterocytes and suppressed hepatic mRNA expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1by ileal FGF19 expression both in an liver X receptor α (LXRα)-mediated manner. In the hyperlipidemic mouse models, the oral administration of peptides reduced serum cholesterol levels through elevation of the ABCG5 expression in proximal intestine and fecal cholesterol secretion. Besides this, peptides induced ileal expression of fibroblast growth factor 15/19 (FGF15/19) and inhibited hepatic bile acid synthesis. We found that the oral treatment of casein-derived bioactive peptides could improve hyperlipidemia by regulating intestinal excretion and hepatic synthesis of cholesterols.

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Section: Discussionsupporting

confidence: 92%

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Lee

Youn

2020

Nutrients

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“…The Lf doses in clinical trials ranged from 200 to 3600 mg day −1 , [ 30–35 ] and mainly concentrated in 1 g day −1 , [ 31–34 ] which is equal to decuple daily dose. In the previous studies, the Lf intervention doses were usually very high, [ 12,19,21 ] whereas the effects of Lf at daily dose on disease prevention have not been fully determined. Considering the ethanol‐caused potential risks of food consumption reduction and malnutrition, [ 22 ] we used AIN‐93G as the control diet and elevated Lf proportion in total protein.…”

Section: Discussionmentioning

confidence: 99%

“…In some studies on the health‐protective effects of Lf, the intervention doses were too high to reach via normal diet. [ 12,19–21 ] Additionally, Lf was usually administrated as an additional supplement instead of replacing the dietary basic protein, which could not exclude the effects of additional protein supplement on disease prevention.…”

Section: Introductionmentioning

confidence: 99%

Daily Dose of Bovine Lactoferrin Prevents Ethanol‐Induced Liver Injury and Death in Male Mice by Regulating Hepatic Alcohol Metabolism and Modulating Gut Microbiota

Liu

Qian

Yang

et al. 2021

Molecular Nutrition Food Res

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Scope Lactoferrin (Lf) possess a protective potential to liver, but whether it can prevent alcoholic liver injury (ALI) remains unclear. Methods and Results Four groups of male C57BL/6J mice are fed with different diets, namely, AIN‐93G diet for control (CON) and ethanol (EtOH) groups, and AIN‐93G diet with 0.4% and 4% casein replaced by Lf for low‐dose Lf (LLf) and high‐dose Lf (HLf) groups, respectively. ALI is induced by giving 20% ethanol ad libitum combined with four “binges”. Lf can remarkably decrease EtOH‐induced mortality. Lf promotes aldehyde dehydrogenase‐2 (ALDH2) expression and suppressing cytochrome P450 2E1 (CYP2E1) overexpression, resulting in the reduced hepatic superoxide and inflammation levels, which ultimately leads to the hepatic injury alleviation. However, HLf increases acetyl‐CoA carboxylase and fatty acid synthase protein levels, which suggests that excessive intake may weaken the beneficial effects of Lf. Moreover, LLf increases the relative abundances of Akkermansia and Lactobacillus. Additionally, the study shows that Lf likely exerts action in its digestive product forms rather than intact Lf molecular in normal condition. Conclusion LLf can ameliorate ALI, which is associated with the regulation of hepatic alcohol metabolism and the modulation of gut microbiota. However, excessive Lf intake may result in a diminished benefit.

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“…[ 38 ] In the liver, activated FXR induces the expression of SHP, which inhibits the expression of CYP7A1 in transcriptional level. [ 39 ] A previous study found that anthocyanins increased mRNA expression of CYP7A1 in liver and activated the conversion of cholesterol to bile acids in hamsters. [ 40 ] Primary bile acid, namely cholic acid and chenodeoxycholic acid, can be transformed into secondary bile acids (deoxycholic acid, lithocholic acid) by bacterial metabolites.…”

Section: Discussionmentioning

confidence: 99%

Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High‐Fat and Cholesterol Diet

Wang

Liu

et al. 2020

Molecular Nutrition Food Res

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Scope: This study explores the beneficial effects of dietary supplementation of black rice anthocyanin extract (BRAE) on cholesterol metabolism and gut dysbiosis. Methods and results: C57BL/6J mice are grouped into the normal chow diet group (NCD), the high-fat and the cholesterol diet group (HCD), and three treatment groups feeding HCD supplemented with various dosage of BRAE for 12 weeks. Results reveal that BRAE alleviates the increased body weight, serum triglyceride (TG), total cholesterol (TC), non-high-density lipoprotein cholesterol levels (non-HDL-C), and increased fecal sterols excretion and caecal short-chain fatty acids (SCFAs) concentration in HCD-induced hypercholesterolemic mice. Moreover, BRAE decreases hepatic TC content through the fundamental regulation of body energy balance gene, adenosine 5′-monophosphate activated protein kinase (AMPK ). Meanwhile, BRAE improves the genes expression involved in cholesterol uptake and efflux, and preserves CYP7A1, ATP-binding cassette subfamily G member 5/8 mRNA expression, and the relative abundance of gut microbiota. Additionally, the antibiotic treatment experiment indicates that the beneficial effects of BRAE in reducing hypocholesterolemia risk largely depends on the gut microbiota homeostasis. Conclusion: BRAE supplement could be a beneficial treatment option for preventing HCD-induced hypocholesterolemia and related metabolic syndromes.

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Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis

Abstract: Lactoferrin (LF) is a multifunctional glycoprotein that can regulate lipid metabolism, lower cholesterol, reduce body weight, and prevent atherosclerosis.

Cited by 22 publications

References 39 publications

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Daily Dose of Bovine Lactoferrin Prevents Ethanol‐Induced Liver Injury and Death in Male Mice by Regulating Hepatic Alcohol Metabolism and Modulating Gut Microbiota

Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High‐Fat and Cholesterol Diet

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