It has been shown that hepatic steatosis, formerly thought to be the start of non-alcoholic fatty liver disease (NAFLD), is actually a healthy increase in triglycerides, whereas free fatty acids are the toxic molecules that lead to steatohepatitis and fibrosis [1,2]. In a mouse model, genetic suppression of the enzyme diacylglycerol acyltransferase 2 (DGAT2) decreased hepatic steatosis while increasing fibrosis due to the toxic effects of FFAs [3]. Lipotoxicity mediated by FFAs (cellular toxicity caused by fat accumulation) in liver cells may originate from the disruption of triglyceride synthesis [4].

NAFLD is a group of diseases that include cirrhosis, steatosis, and steatohepatitis, which are characterized by fatty infiltration of the liver. NAFLD is the most common liver disease, with an estimated prevalence worldwide of around 25% [5]. The current epidemic of obesity and metabolic syndrome, which manifest in the liver as NAFLD, may be responsible for the sudden increase in the incidence of NAFLD [6]. The majority of patients with NAFLD have simple hepatic steatosis without steatohepatitis and fibrosis. In addition, in 2–3% of individuals, NAFLD can become non-alcoholic steatohepatitis (NASH), which can lead to progressive fibrosis, cirrhosis, and consequences such as hepatocellular carcinoma [7,8,9]. As much as 50% of patients with simple steatosis who later develop NASH may also develop severe fibrosis [10].

The parenchyma of the liver is made up of a variety of cell types, the bulk of which are hepatocytes (around 70% of the liver cell population) [11]. Parenchymal cells include hepatocytes and cholangiocytes, while nonparenchymal cells consist of Kupffer cells, stellate cells, and endothelial cells. Hepatic cells orchestrate the development of liver disorders. Hepatocytes, macrophages, and hepatic stellate cells interact in NAFLD and its severe variant, non-alcoholic steatohepatitis (NASH), although the precise methods through which these cells are orchestrated are not fully understood [11,12].

Patients with NAFLD have higher levels of oleic acid, a monounsaturated fatty acid (MUFA), and palmitic acid, according to studies examining the makeup of hepatic and circulatory free fatty acids (a saturated fatty acid (SFA)) [13,14]. However, polyunsaturated fatty acids have not been demonstrated to be toxic to hepatocytes and may even be beneficial in NAFLD patients [15,16]. Experimental research on this subject in human B cells has examined the function of stearoyl-CoA desaturase-1 (SCD1), the enzyme that changes SFA into MUFA [17]. More MUFAs are produced because of the increased expression of SCD1, and these MUFAs are then incorporated into triglycerides to produce simple and well-tolerated hepatic steatosis [18]. However, the removal of SCD1 results in the accumulation of SFA, which in turn triggers hepatocyte death and steatohepatitis [19]. Therefore, the type of FFAs stored in hepatocytes is just as important for developing NAFLD as the amount of FFAs accumulated, if not more [20]. Apoptosis, a form of programmed cellular death, is considered a key mechanism in developing NAFLD [21,22]. The main pathogenic mechanism seen in the biopsy samples of NASH patients is apoptosis, and in the spectrum of NAFLD, the presence of apoptosis helps to identify NASH patients from those with simple steatosis [23]. Patients who have higher levels of apoptosis will have advanced fibrosis because the degree of apoptosis and inflammation are inversely correlated [24]. The correlation between the levels of circulating cytokeratin-18 fragments, which are indicators of apoptotic liver cells, and the degree of fibrosis, provides additional evidence that apoptosis plays a significant role in NASH [25]. Lipoapoptosis is the name given to apoptosis mediated by FFAs [26]. Activation of the apoptotic pathways may occur either by an extrinsic pathway mediated by cell surface receptors or by an intrinsically mediated pathway by intracellular organelles [27].

A fundamental component of NASH is the lipotoxicity of hepatocytes. Lipotoxicity is caused by the accumulation of lipid intermediates, which cause cell malfunction and cell death. In NASH, hepatocytes build up triglycerides and various lipid metabolites, including free cholesterol, ceramides, and free fatty acids (FFA) [28]. Hepatocytes store most fatty acids as triglycerides, and some data suggest that the esterification of fatty acids into neutral triglycerides provides a protection mechanism against lipotoxicity [4,29]. On the other hand, FFA causes liver damage and activates specific signaling stunts, resulting in hepatocytic apoptosis, which in this context is called lipoapoptosis [30]. FFA is thus regarded as a major mediator of the lipotoxicity of hepatocytes. In fact, in NASH, there is an increased hepatic inflow of FFA following increased lipolysis in the peripheral fat tissue due to insulin resistance [31]. The lipotoxicity of FFA in hepatocytes is partially mediated through their intracellular lysophosphatidyl choline metabolite, which has also been seen to increase in the liver of patients with NAFLD in proportion with the severity of the disease [29].

Antihyperlipidemic drugs frequently cause mixed hepatocellular or liver lesions, with rare cases of pure cholestatic image [32,33]. The cytochrome P450 system, bile acid transport protein dysfunction, immune-mediated inflammatory response to the drug or its metabolites, immune-mediated apoptosis by tumor necrosis factor, and oxidative stress as a result of intracellular damage are some of the various proposed mechanisms of hepatotoxicity that vary depending on the drug or drug class [34].

2. Mediators of Hepatotoxicity from Excess of Lipids

2.1. Toll-like Receptors

2.2. Death Receptors

2.3. Mitochondrial Dysfunction and Reactive Oxygen Species

2.4. Lysosomal Permeabilization

2.5. Endoplasmic Reticulum Stress