Abstract
Steatosis is a liver lesion reported with numerous pharmaceuticals. Prior studies showed that severe impairment of mitochondrial fatty acid oxidation (mtFAO) constantly leads to lipid accretion in liver. However, much less is known about the mechanism(s) of drug-induced steatosis in the absence of severe mitochondrial dysfunction, although previous studies suggested the involvement of mild-to-moderate inhibition of mtFAO, increased de novo lipogenesis (DNL), and impairment of very low-density lipoprotein (VLDL) secretion. The objective of our study, mainly carried out in human hepatoma HepaRG cells, was to investigate these 3 mechanisms with 12 drugs able to induce steatosis in human: amiodarone (AMIO, used as positive control), allopurinol (ALLO), d-penicillamine (DPEN), 5-fluorouracil (5FU), indinavir (INDI), indomethacin (INDO), methimazole (METHI), methotrexate (METHO), nifedipine (NIF), rifampicin (RIF), sulindac (SUL), and troglitazone (TRO). Hepatic cells were exposed to drugs for 4 days with concentrations decreasing ATP level by less than 30% as compared to control and not exceeding 100 × Cmax. Among the 12 drugs, AMIO, ALLO, 5FU, INDI, INDO, METHO, RIF, SUL, and TRO induced steatosis in HepaRG cells. AMIO, INDO, and RIF decreased mtFAO. AMIO, INDO, and SUL enhanced DNL. ALLO, 5FU, INDI, INDO, SUL, RIF, and TRO impaired VLDL secretion. These seven drugs reduced the mRNA level of genes playing a major role in VLDL assembly and also induced endoplasmic reticulum (ER) stress. Thus, in the absence of severe mitochondrial dysfunction, drug-induced steatosis can be triggered by different mechanisms, although impairment of VLDL secretion seems more frequently involved, possibly as a consequence of ER stress.
Highlights
Steatosis is a frequent liver lesion reported in different hepatic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C virus infection, and druginduced liver injury (DILI) (Amacher and Chalasani 2014; Seitz et al 2018; Allard et al 2019)
When HepaRG cells were treated for 4 days with the 12 selected steatogenic drugs, 9 of them induced a significant accumulation of neutral lipids, namely AMIO, ALLO, 5FU, INDI, INDO, METHO, SUL, RIF, and TRO (Fig. 1)
Whereas profound mitochondrial dysfunction is involved in rare individuals with predisposing factors, most cases of steatosis are benign (Amacher and Chalasani 2014; Fromenty 2019; Fromenty and Pessayre 1995)
Summary
Steatosis ( referred to as fatty liver) is a frequent liver lesion reported in different hepatic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C virus infection, and druginduced liver injury (DILI) (Amacher and Chalasani 2014; Seitz et al 2018; Allard et al 2019). Previous studies suggested the involvement of mild-to-moderate inhibition of mitochondrial fatty acid oxidation (mtFAO), increased de novo lipogenesis (DNL), and impairment of very low-density lipoprotein (VLDL) secretion (Fromenty 2019; Begriche et al 2011; Lettéron et al 2003; Tolosa et al 2016; Grünig et al 2018; Rooney et al 2019). These mechanisms are not mutually exclusive and some drugs might alter two or three of these metabolic pathways. The antianginal and antiarrhythmic drug amiodarone (AMIO) and the antibiotic tetracycline were shown to inhibit mtFAO (Fromenty and Pessayre 1995), but these drugs might favor DNL via the activation of sterol regulatory element binding protein-1 (SREBP1) (Anthérieu et al 2011; Corton 2019)
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