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Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).
]. In addition, DILI can lead to the withdrawal of drugs from the market or earlier during clinical trials, thus causing huge financial losses. A recent retrospective study indicates that the risk of DILI is enhanced when the administered daily dosage is higher than 50 mg or when the drug undergoes significant liver metabolism [
]. Mitochondrial dysfunction is a generic term, which includes alteration of different metabolic pathways and damage to mitochondrial components. In addition, these mitochondrial disturbances can have a variety of deleterious consequences, such as oxidative stress, energy shortage, accumulation of triglycerides (steatosis), and cell death. Regarding steatosis, recent investigations suggest that besides mitochondrial dysfunction several other mechanisms could be involved. Before discussing the main mechanisms involved in drug-induced mitochondrial dysfunction and lipid dysmetabolism, we shall recall some important features pertaining to the central role of mitochondria in cell death and energy homeostasis. We will also bring to mind some aspects of lipid metabolism not directly related to mitochondria and the most relevant effects of the adipose hormones adiponectin and leptin on liver function. Finally, this review will also evoke the main factors that could predispose some patients to DILI, in particular when hepatotoxicity is due to mitochondrial dysfunction or due to impaired lipid homeostasis.
Mitochondrial structure and functions
Mitochondrial membrane permeabilization and cell death
Mitochondria are organelles with two membranes surrounding a space (matrix) containing various enzymes and the mitochondrial genome (mtDNA) (Fig. 1). The inner membrane, which also harbors many enzymes, behaves as a barrier that is poorly permeable to various molecules [
]. Thus, this membrane contains transporters allowing the entry of endogenous compounds (ADP, fatty acids, glutathione, pyruvic acid) and possibly xenobiotics as well.
In some pathophysiological circumstances, the mitochondrial membranes can lose their structural and functional integrity, in particular after the opening of the mitochondrial permeability transition pores (MPTP) [
]. These pores involve at least 4 candidate proteins, namely the peripheral benzodiazepine receptor (PBR), the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase (ANT), and cyclophilin D [
]) is able to bind the immunosuppressive drug cyclosporin A that therefore reduces the opening probability of the MPTP. In contrast, several drugs and toxic compounds, but also high levels of some endogenous derivatives (e.g. calcium, fatty acids, and bile salts) can induce MPTP opening. As the latter event strongly alters mitochondrial function and structure, it can endanger cell life. However, the exact pathway whereby the cell will die (namely apoptosis or necrosis) depends on the number of mitochondria harboring opened MPTP [
Indeed, MPTP opening can profoundly disturb ATP synthesis, through the loss of inner mitochondrial membrane integrity. If numerous mitochondria present opened MPTP, ATP stores will slump rapidly and necrosis will occur through a sudden rise in intracellular calcium levels because ATP is mandatory for the activity of the plasma membrane calcium ATPase (PMCA), an enzyme responsible for calcium extrusion out of the cell. In contrast, if MPTP opening takes place only in some mitochondria, ATP levels will be maintained thanks to undamaged organelles. However, the rare mitochondria involved in MPTP opening will swell allowing the release of different pro-apoptotic proteins including the apoptosis inducing factor (AIF), several caspases, and cytochrome c [
]. This key protein of the respiratory chain (Fig. 1), when released in the cytoplasm, can bind to the Apaf-1 protein and ATP thus initiating the apoptotic pathway through the activation of caspases 9 and 3. Consequently, MPTP opening in a few mitochondria can also have deleterious consequences [
Several important points must be discussed regarding mitochondrial membrane permeabilization. Firstly, MPTP opening initially permeabilizes the mitochondrial inner membrane without alteration of the outer membrane. However, MPTP opening causes an equilibration of solutes with molecular masses up to 1500 Da and the massive entry of water into the matrix, which causes unfolding of the inner membrane and mitochondrial swelling. The latter event thus induces outer membrane rupture and the release of several mitochondrial proteins located in the intermembrane space (e.g. cytochrome c and AIF), which trigger apoptotis [
]. This scenario requires the formation of pores within this membrane thanks to the association of two pro-apoptotic proteins belonging to the Bcl-2 family, namely Bak (already located in the outer membrane) and Bax (which is recruited from the cytosol) [
]. Thus, whatever the mechanism involved in membrane permeabilization, this event can strongly alter mitochondrial function and structure, and thus lead to cell death. Finally, it is noteworthy that the MPTP structure seems to be different from one tissue to another. This may explain why some organs could be more or less vulnerable to certain permeability transition inducers [
]. Mitochondrial ATP synthesis is possible thanks to the oxidative degradation of endogenous substrates, such as pyruvate (generated from glycolysis), fatty acids, and amino acids. Pyruvate oxidation takes place in the tricarboxylic acid cycle (TCA, also called Krebs cycle), whereas fatty acid degradation within mitochondria is mediated by β-oxidation (Fig. 1).
In order to undergo the β-oxidation pathway fatty acids must cross the mitochondrial membranes. Whereas short-chain and medium-chain fatty acids freely enter the mitochondria, long-chain fatty acids (LCFAs) can cross the mitochondrial membranes only by means of a multienzymatic system requiring coenzyme A and l-carnitine as cofactors (Fig. 1). In this system, carnitine palmitoyltransferase 1 (CPT1) catalyses the rate limiting step of LCFA oxidation as this enzyme can be strongly inhibited by malonyl-CoA, an endogenous derivative synthesized during de novo lipogenesis [
Inside the mitochondria, short-chain and medium-chain fatty acids are activated in acyl-CoA molecules by specific acyl-CoA synthases, whereas long-chain fatty acyl-carnitine intermediates are transformed back to their corresponding acyl-CoA thioesters thanks to CPT2 (Fig. 1). Whatever the length of their carbon chain, acyl-CoA derivatives are then cut down sequentially thanks to the β-oxidation process that generates acetyl-CoA moieties and shorter fatty acids that enter new β-oxidation cycles (Fig. 1). These acetyl-CoA moieties are immediately used for the synthesis of ketone bodies (mainly acetoacetate and β-hydroxybutyrate) released in the blood and oxidized in extra-hepatic tissues, such as kidney, muscle, and brain (Fig. 1). Because mitochondrial β-oxidation and ketogenesis play a fundamental role in energy homeostasis [
]. Indeed, several dehydrogenases involved in the TCA cycle and β-oxidation are using NAD+ and FAD to generate NADH and FADH2, which give their electrons and protons to the mitochondrial respiratory chain (MRC) (Fig. 1). Electrons are sequentially transferred to different multi-protein complexes of the MRC and finally to cytochrome c oxidase (complex IV), which safely reduces oxygen into water in the presence of protons (Fig. 1). Importantly, electron transfer within MRC is associated with the ejection of protons from the matrix to the intermembrane space of the mitochondria, thus generating a large membrane potential Δψm [
]. When cells need energy, protons are reentering the matrix thanks to the F0 portion of the ATP synthase (complex V) thus releasing part of the potential energy of Δψm. This energy is then used by the F1 portion of the ATP synthase for the phosphorylation of ADP into ATP (Fig. 1). Some drugs able to abolish ADP phosphorylation (and thus ATP synthesis) without inhibiting substrate oxidation are referred to as oxidative phosphorylation (OXPHOS) uncouplers [
]. Indeed, a small fraction of electrons entering the MRC can prematurely escape from complexes I and III and directly react with oxygen to generate the superoxide anion radical. This radical is then dismutated by the mitochondrial manganese superoxide dismutase (MnSOD) into hydrogen peroxide (H2O2), which is detoxified into water by the mitochondrial glutathione peroxidase (GPx) that uses reduced glutathione (GSH) as a cofactor. Hence, in the normal (non-diseased) state, most of the ROS generated by the MRC are detoxified by the mitochondrial anti-oxidant defenses. The remaining (i.e. non-detoxified) ROS diffuse out of mitochondria and serve as second messengers to trigger cellular processes such as mitogenesis [
However, this detoxification process can be overwhelmed in different pathophysiological circumstances. This occurs in particular in case of GSH depletion within liver mitochondria, which reduces greatly their capability to detoxify H2O2 since they do not have catalase [
]. Depletion of mitochondrial GSH below a critical threshold thus favors H2O2 accumulation by impairing its detoxification. This in turn triggers mitochondrial dysfunction, MPTP opening, activation of c-Jun-N-terminal kinase (JNK), and cell death [
]. Chronic ethanol intoxication, fasting, and malnutrition are diseased states favoring GSH depletion, in particular within mitochondria.
Mitochondrial anti-oxidant enzymes can also be overwhelmed when MRC is chronically impaired. Indeed, a partial block in the flow of electrons greatly increases the probability of monoelectronic reduction of oxygen and superoxide anion production within the complexes I and III [
]. Whereas the most part of these polypeptides are encoded by the nuclear genome and subsequently imported within the mitochondria, 13 MRC polypeptides are instead encoded by the mitochondrial genome, a small piece of circular doubled-stranded DNA located within the mitochondrial matrix (Fig. 1). In a single cell there are several hundred (or thousand) copies of mtDNA whose replication occurs continuously, even in cells that do not divide [
Most cells (including hepatocytes) have a surplus of mtDNA copies, and can, therefore, tolerate a substantial depletion of mtDNA. Classically, it is considered that the number of normal mtDNA copies must fall below 20–40% of basal levels to induce mitochondrial dysfunction and severe adverse events [
]. The few mtDNA copies remaining within each mitochondrion are not able to provide enough MRC polypeptides, thus leading to OXPHOS impairment and secondary inhibition of mitochondrial FAO and TCA cycle. Another key feature of mtDNA is its high sensitivity to ROS-induced oxidative damage and mutations due to its proximity to the inner membrane (a major source of ROS), the absence of protective histone, and an incomplete repertoire of mitochondrial DNA repair enzymes [
Lipid and carbohydrate metabolism in extramitochondrial compartments
Besides mitochondria, other organelles (or extra-mitochondrial enzyme systems) can be involved in FAO. For instance, peroxisomes degrade long-chain and very long-chain fatty acids but not medium-chain and short-chain fatty acids. The first step of peroxisomal FAO continuously generates H2O2 through acyl-CoA oxidase (ACO) activity [
Mitochondrial, peroxisomal, and microsomal FAO is strongly regulated by peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor and transcription factor, which can be stimulated by endogenous fatty acids or synthetic drugs (fibrates) [
]. PPARα stimulation increases the expression of the mitochondrial enzymes CPT1, medium-chain acyl-CoA dehydrogenase (MCAD) and HMG-CoA synthase (involved in ketone body synthesis), the peroxisomal ACO, and the microsomal CYP4A [
]. Besides PPARα, other transcription factors regulating hepatic FAO include forkhead box A2 (FoxA2) and cAMP-response element-binding protein (CREB) that are activated during fasting periods by low insulinemia and high glucagonemia, respectively [
On the contrary, the metabolic and hormonal context after a meal favors lipid synthesis with a concomitant reduction of the FAO pathway. Indeed, high plasma levels of insulin and glucose, respectively, activate the sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate responsive element-binding protein (ChREBP) that both increase the hepatic expression of key enzymes involved in glycolysis (e.g. glucokinase and l-pyruvate kinase) and de novo lipogenesis (e.g. acetyl-CoA carboxylase and fatty acid synthase). Lipogenesis is associated with the accumulation of the CPT1 inhibitor malonyl-CoA, thus reducing the flux of mitochondrial LCFA oxidation [
It is worthy to mention herein that hepatic SREBP-1c and ChREBP can be abnormally activated in obese and diabetic individuals thus favoring fatty liver. Another mechanism that could contribute to fatty liver in these patients is the permanent and unrepressed triglycerides lipolysis taking place in the expanded adipose tissue (due to insulin resistance), which leads to a massive influx of free fatty acids in the hepatocytes [
]. Besides SREBP-1c and ChREBP, other transcription factors could play a significant role in de novo lipogenesis (at least in some metabolic contexts) such as PPARγ and pregnane X receptor (PXR). Both transcription factors are nuclear receptors that can be activated by different endogenous and exogenous ligands [
Once synthesized, fatty acids combine with glycerol to generate triglycerides. These lipids are subsequently incorporated into VLDL particles, which are normally secreted into the plasma unless this route of lipid secretion is impaired. VLDL synthesis requires not only triglycerides but also apolipoproteins B and CIII. Furthermore, VLDL assembly within the endoplasmic reticulum requires the microsomal triglyceride transfer protein (MTP) whose expression is reduced by insulin [
]. In the plasma, VLDL particles are hydrolyzed by lipoprotein lipase (LPL), thus allowing the release of free fatty acids that will be either oxidized in different extra-hepatic tissues (e.g. heart, skeletal muscles) or re-esterified into triglycerides in the adipose tissue. LPL is usually not expressed in the adult liver except in some pathophysiological situations such as obesity [
Impact of leptin and adiponectin on lipid and carbohydrate metabolism
Besides insulin and glucagon, hormones secreted by the adipose tissue (referred to as adipokines) can also play a salient role in lipid homeostasis. Among these adipokines, leptin, and adiponectin present an “anti-steatotic” action by decreasing de novo lipogenesis and activating mitochondrial FAO, in particular by reducing the intracellular levels of malonyl-CoA [
]. Indeed, leptin and adiponectin can induce the phosphorylation of the lipogenic enzyme acetyl-CoA carboxylase (ACC), thus leading to its inactivation and the subsequent reduction of malonyl-CoA synthesis [
]. However, total leptin deficiency is particularly rare in humans. In contrast, common obesity is associated with high leptinemia (a consequence of leptin resistance) and low adiponectinemia, which plays a major role in the pathophysiology of type 2 diabetes and fatty liver [
Drug-induced mitochondrial dysfunction and liver injury
Drug-induced adverse events and mitochondrial toxicity
The view that drugs could disturb mitochondrial function emerged several decades ago when clinical studies reported in some medicated individuals the occurrence of symptoms usually observed in patients presenting a mitochondrial disease of genetic origin or a Reye’s syndrome (whose physiopathology involves severe mitochondrial dysfunction) [
]. Likewise, myopathy, lactic acidosis, and hepatic steatosis have been reported in the late 80’s and early 90’s in patients treated with the antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (AZT), zalcitabine (ddC), didanosine (ddI) and stavudine (d4T) [
]. Since then, the list of drugs inducing adverse events due to mitochondrial dysfunction has not ceased to grow year after year.
Regarding drug-induced liver diseases, different mechanisms of mitochondrial dysfunction have been described thus far, including membrane permeabilization, OXPHOS impairment, FAO inhibition, and mtDNA depletion (Table 1) [
]. Importantly, DILI due to mitochondrial toxicity has led to the interruption of clinical trials, or drug withdrawal after marketing, in particular when the benefit/risk ratio was deemed to be too low for the patient’s healthiness (Table 2). Moreover, some marketed drugs have received Black Box warnings from drug agencies due to mitochondrial dysfunction and related hepatotoxicity (Table 3) [
Table 1Hepatotoxic drugs and their corresponding deleterious effects on mitochondrial function and genome. Note that the absence of cross indicates that the toxic effect has not been reported to date for the corresponding drug and that for different compounds listed below some of the mitochondrial effects have been observed only in vitro.
Drug-induced mitochondrial alterations and cytolytic hepatitis
Cytolytic hepatitis encompasses a wide spectrum of liver injury of different severity since the destruction of hepatocytes (i.e. cytolysis) can involve a variable amount of the hepatic mass. Consequently, the mildest forms are characterized by an isolated increase in plasma alanine aminotransferase (ALT) and asparate aminotransferase (AST), whereas in the most severe cases fulminant hepatitis can occur thus requiring liver transplantation [
]. As already mentioned, hepatocyte cytolysis occurring in vivo can be the consequence of necrosis or apoptosis. While necrosis leads to the destruction of the plasma membrane and the release in the extracellular milieu of different cell components such as transaminases and lactate dehydrogenase (LDH), apoptosis is generally associated with a discreet removal of the dying cells by neighboring macrophages [
]. Studies pertaining to drug-induced MPTP are sometimes performed in mitochondria de-energized with oligomycin and in the presence of high concentrations of calcium (e.g. from 10 to 50 μM). Since these conditions have a profound impact on MPTP opening [
], it is difficult to extrapolate some data to the in vivo situation.
The precise mechanisms whereby drugs can induce MPTP opening are not known although recent investigations suggest at least three hypotheses, which are not mutually exclusive.
Firstly, drugs can interact with some MPTP components. For instance, alpidem could trigger mitochondrial membrane permeabilization and cell death through its binding to PBR which is located on the outer membrane [
]. As regards APAP, it is, however, unclear whether this drug induces MPTP opening via GSH depletion, or through the direct interaction of its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) with some (still uncharacterized) MPTP components. Indeed, NAPQI is able to bind covalently to mitochondrial proteins and this could have deleterious effect not only on MPTP but also on mitochondrial respiration and FAO [
]. Regarding APAP, several studies suggest that JNK activation is related to ROS generation and, therefore, APAP-induced oxidative stress could promote MPTP opening through direct and indirect pathways [
Drugs can also induce cell death through a direct impairment of OXPHOS (Table 1), which reduces ATP synthesis. As already mentioned, severe ATP depletion inhibits calcium extrusion from the cell thus leading to its intracellular accumulation. This in turn activates proteases, endonucleases, and phospholipases that participate in the destruction (or the disorganization) of cell constituents including the plasma membrane and cytoskeleton, thus leading to necrosis [
]. In fact, drug-induced OXPHOS impairment can occur through different mechanisms.
The first mechanism is OXPHOS uncoupling without subsequent inhibition of the MRC. In this case, substrate oxidation is maintained (since electron transfer within the MRC is not altered) although ATP synthesis is strongly hindered. Indeed, OXPHOS uncouplers are usually protonophores, namely molecules that are protonated in the mitochondrial intermembrane space thus generating cationic compounds that take advantage of the membrane potential Δψm to cross the inner membrane. Consequently, protons are entering the matrix independently of ATP synthase thus causing a drop of ATP synthesis. Drugs that induce OXPHOS uncoupling without subsequent inhibition of the MRC are for instance the nonsteroidal anti-inflammatory drug (NSAID) nimesulide and the anti-Alzheimer drug tacrine [
]. Finally, OXPHOS uncoupling can be associated with other mitochondrial effects that present a more harmful impact on cell viability. For instance, although diclofenac both uncouples OXPHOS and favors MPTP opening only the latter effect could be responsible for cell injury [
The second mechanism is OXPHOS uncoupling with subsequent inhibition of the MRC activity, thus leading to a secondary impairment of substrate oxidation such as FAO. Unfortunately, the precise mechanism whereby these drugs alter electron transfer within the MRC is unknown. Actually, the dual effect of some drugs on OXPHOS (i.e. uncoupling followed by inhibition) seems to be concentration-dependent and “isolated” uncoupling nevertheless can be observed for low concentrations of these drugs. Drug-induced dual effect on OXPHOS has been described with amiodarone, perhexiline, alpidem, tamoxifen, and buprenorphine [
]. Finally, while drug-induced MRC blockage can participate in the inhibition of mitochondrial FAO, some drugs, such as amiodarone, perhexiline, and tamoxifen can also directly inhibit FAO enzymes such as CPT1, as discussed below [
], which is sometimes referred to as microsteatosis. Microvesicular steatosis is a potentially severe liver lesion that can be associated with liver failure, encephalopathy, and profound hypoglycemia thus leading to the death of some patients. Liver pathology shows the presence of numerous cytoplasmic lipid droplets, which can be stained with oil red O [
], most often provokes macrovacuolar steatosis (occasionally associated with microvesicular steatosis) and steatohepatitis. Microvesicular steatosis or mixed steatosis has seldom been reported with troglitazone in addition to other lesions, such as necroinflammation, fibrosis, and cholestasis [
], these additional mechanisms most probably play a secondary role in the pathophysiology and severity of microvesicular steatosis.
A primary consequence of severe inhibition of mitochondrial FAO is an accumulation of fatty acids that are either esterified into triglycerides or that remain as a free form, which can reinforce mitochondrial dysfunction (Fig. 2) [
]. Another major consequence is an impairment of energy output in the liver but also in extra-hepatic tissues attributable to lower ketone body production (or utilization). Importantly, reduced mitochondrial FAO hampers hepatic gluconeogenesis as a consequence of ATP shortage and pyruvate carboxylase inhibition, which can lead to severe hypoglycemia in some individuals (Fig. 2) [
]. Finally, severe impairment of mitochondrial FAO is associated with an accumulation in plasma and urines of fatty acid derivatives, such as acyl-carnitine and acyl-glycine esters and dicarboxylic acids [
Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates.
]. Unfortunately, the FAO enzymes inhibited by these drugs have not always been identified, although CPT1 (Fig. 1) could be a key target. Indeed, this enzyme can be inhibited by VPA (Fig. 3), amiodarone, and tamoxifen [
Secondly, drugs can impair mitochondrial FAO through the generation of coenzyme A and/or l-carnitine esters, thus decreasing the levels of these major FAO cofactors (Fig. 1). This mechanism has been shown for VPA (Fig. 3), salicylic acid, and ibuprofen [
]. Indeed, the MRC allows the constant regeneration of FAD and NAD+ required for the enzymatic reactions catalyzed, respectively, by the FAO enzymes acyl-CoA dehydrogenases and 3-hydroxyacyl-CoA dehydrogenases (Fig. 1). Inhibition of FAO secondarily to MRC impairment could occur with amiodarone (Fig. 4), perhexiline, tamoxifen, and buprenorphine [
]. Interestingly, these amphiphilic drugs can be protonated within the intermembrane space of the mitochondria thus generating cationic compounds entering the matrix thanks to the membrane potential Δψm (Fig. 4) [
]. Besides OXPHOS uncoupling, this allows their mitochondrial accumulation and the subsequent inhibition of both FAO and MRC enzymes. Whereas relatively low concentrations of these amphiphilic drugs can inhibit directly FAO enzyme(s), higher concentrations are required in order to impair the MRC [
], it is still unclear whether these drugs inhibit mitochondrial FAO through MRC impairment or by a direct mechanism.
Fourthly, drugs can impair mitochondrial FAO and induce microvesicular steatosis by reducing mtDNA levels (Table 1). Indeed, profound mtDNA depletion induces MRC impairment and secondary inhibition of FAO. This has been shown for the antiviral fialuridine (FIAU), AZT, d4T, and ddI, which all inhibit the mtDNA polymerase γ [
Fialuridine and its metabolites inhibit DNA polymerase γ at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts.
], liver triglycerides accumulate as a large (often single) lipid vacuole displacing the nucleus at the periphery of the hepatocyte. This liver lesion is commonly referred to as macrovacuolar steatosis [
]. Several drugs responsible for this hepatic lesion can also induce a mixed form of fat accumulation with macrovacuolar steatosis in some hepatocytes and microvesicular steatosis in others. It is possible that the size of the fat droplets could depend on the nature of some proteins wrapping the lipids (e.g. perilipin and adipophilin) and/or their content in free fatty acids [
Macrovacuolar steatosis is also observed in a large number of obese and diabetic patients, even in those that do no drink alcohol. That is why it is often referred to as nonalcoholic fatty liver in the context of obesity and related metabolic disorders [
]. In these disorders, hepatic steatosis primarily results from two mechanisms: 1) an increased delivery of free fatty acids to the liver which is the consequence of insulin resistance in adipose tissue (that favors triglycerides hydrolysis); and, 2) a stimulation of de novo hepatic lipogenesis, which is mainly due to hyperinsulinemia and hyperglycemia that activate the transcription factors SREBP-1c and ChREBP, respectively [
]. Ethanol-induced fatty liver results from different mechanisms including increased hepatic uptake of fatty acids and de novo lipogenesis, impaired PPARα signaling, mitochondrial dysfunction and reduced secretion of triglycerides [
]. Some of these effects could be due to reduced adiponectin secretion by the adipose tissue and elevated expression of tumor necrosis factor-α (TNFα, which both favor lipid synthesis and reduced mitochondrial FAO [
]. Interestingly, small molecules inhibiting MTP have been tested in order to lower blood lipids, but the clinical usefulness of this therapeutic strategy has been hampered by their potential to induce hepatic steatosis [
Thirdly, increased cellular uptake of fatty acids could play a significant role with some compounds. This mechanism has been proposed for efavirenz which activates AMP-activated protein kinase (AMPK) most probably as a consequence of mitochondrial complex I inhibition and reduced ATP synthesis [
], a potentially severe liver lesion characterized by the presence of necroinflammation, fibrosis, and Mallory bodies. In the context of drug-induced steatohepatitis, fat accumulates usually as large vacuoles, although microvesicular steatosis can also be present in some hepatocytes. Inflammation and fibrosis can be of variable severity and occasionally cirrhosis occurs with drugs, such as amiodarone, perhexiline, and didanosine [
]. Importantly, drug-induced steatohepatitis shares many pathological and clinical features with alcoholic steatohepatitis and nonalcoholic steatohepatitis (NASH).
Although there are still some unsolved issues about the mechanisms involved in the progression of steatosis into steatohepatitis, there is evidence for a key role of mitochondrial dysfunction (Fig. 5). Indeed, several drugs causing steatohepatitis are able to impair the mitochondrial OXPHOS process and inhibit the MRC (Fig. 5) [
]. Actually, inhibition of the MRC could not only participate to fat deposition but also to ROS overproduction. However, other (i.e. nonmitochondrial) sources of ROS are probably involved, such as peroxisomal FAO, or microsomal CYPs [
Hardwick JP, Osei-Hyiaman D, Wiland H, Abdelmegeed MA, Song BJ. PPAR/RXR regulation of fatty acid metabolism and fatty acid ω-hydroxylase (CYP4) isozymes: implications for prevention of lipotoxicity in fatty liver disease. PPAR Res 2009;2009:952734, doi:10.1155/2009/952734.
ROS, whatever their sources, can then trigger peroxidation of polyunsaturated fatty acids, a degradative process generating reactive aldehydic derivatives, such as malondialdehyde and 4-hydroxynonenal [