Effects of medium‐ and long‐chain fatty acids on acetaminophen‐ or rifampicin‐induced hepatocellular injury

Yang, Jun; Peng, Ting; Huang, Jiyong; Zhang, Guohua; Xia, Jiaheng; Ma, Maomao; Deng, Dewei; Gong, Deming; Zeng, Zheling

doi:10.1002/fsn3.1641

Cited by 4 publications

(5 citation statements)

References 55 publications

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“…Although it is known that MCFAs and MCTs have antiinflammatory effects and that GPR84 is coupled with inhibitory G proteins (Gi/o) ( 33 , 34 ), recent in vitro studies have described GPR84 as a proinflammatory receptor ( 35 – 37 ). However, since these studies were conducted using only potent synthetic GPR84 agonists, the physiological activity of GPR84 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Ohue‐Kitano¹,

Nonaka²,

Nishida³

et al. 2023

JCI Insight

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Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. GPR84 acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84-signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84deficient mice exhibited non-alcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage over-activation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake-induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Exogenous GPR84 stimulation is therefore a potential strategy for treating NASH.

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Section: Discussionmentioning

confidence: 99%

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Ohue‐Kitano¹,

Nonaka²,

Nishida³

et al. 2023

JCI Insight

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“…DILI is the primary reason for poor drug approval rates and drug withdrawal; it is also the most common severe adverse reaction to anti-TB therapy (Yang et al, 2020a). In a 14-days study on RIF dosing in mice, accumulation of lipids due to upregulation of peroxisome proliferator-activated receptor-γ was found to be the primary cause of RIF-induced toxicity at 177 mg/kg (LD 10 , equivalent to approximately 20 mg/kg in humans), while 442.5 mg/kg RIF caused another type of unspecified liver damage (LD 25 , equivalent to approximately 50 mg/kg in humans) (Kim et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Screening of Biomarkers and Toxicity Mechanisms of Rifampicin-Induced Liver Injury Based on Targeted Bile Acid Metabolomics

Deng

Luo

et al. 2022

Front. Pharmacol.

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Rifampicin (RIF) is a critical first-line drug for tuberculosis. However, long-term or high-dose treatment with RIF can induce severe liver injury; the underlying mechanism of this effect has not yet been clarified. This study was performed to screen reliable and sensitive biomarkers in serum bile acids (BAs) using targeted BA metabolomics and evaluate the toxicity mechanisms underlying RIF-induced liver injury through the farnesoid x receptor (Fxr)-multidrug resistance-associated proteins (Mrps) signaling pathway. Thirty-two Institute of Cancer Research mice were randomly divided into four groups, and normal saline, isoniazid 75 mg/kg + RIF 177 mg/kg (RIF-L), RIF-L, or RIF 442.5 mg/kg (RIF-H) was orally administered by gavage for 21 days. After treatment, changes in serum biochemical parameters, hepatic pathological conditions, BA levels, Fxr expression, and BA transporter levels were measured. RIF caused notable liver injury and increased serum cholic acid (CA) levels. Decline in the serum secondary BAs (deoxycholic acid, lithocholic acid, taurodeoxycholic acid, and tauroursodeoxycholic acid) levels led to liver injury in mice. Serum BAs were subjected to metabolomic assessment using partial least squares discriminant and receiver operating characteristic curve analyses. CA, DCA, LCA, TDCA, and TUDCA are potential biomarkers for early detection of RIF-induced liver injury. Furthermore, RIF-H reduced hepatic BA levels and elevated serum BA levels by suppressing the expression of Fxr and Mrp2 messenger ribonucleic acid (mRNA) while inducing that of Mrp3 and Mrp4 mRNAs. These findings provide evidence for screening additional biomarkers based on targeted BA metabolomics and provide further insights into the pathogenesis of RIF-induced liver injury.

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“…Two other studies were performed in hepatocyte cell lines incubated with different fatty acids. In the first study, carried out in L02 liver cells, the investigations showed that a 24 h exposure to the monounsaturated oleic acid (C18:1) exacerbated APAP cytotoxicity whereas different medium chain fatty acids did not cause this effect [ 73 ]. Unfortunately, this study did not determine whether these different fatty acids induced steatosis in L02 liver cells.…”

Section: Apap Hepatotoxicity In Nafldmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Begriche¹,

Penhoat²,

Bernabeu-Gentey³

et al. 2023

Livers

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The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

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Effects of medium‐ and long‐chain fatty acids on acetaminophen‐ or rifampicin‐induced hepatocellular injury

Cited by 4 publications

References 55 publications

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Screening of Biomarkers and Toxicity Mechanisms of Rifampicin-Induced Liver Injury Based on Targeted Bile Acid Metabolomics

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

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