In the present study, we have tested the effects of inhibiting GDS synthesis in two different hepatic steatosis models: HFD which increases fatty acid influx in the liver and MCD diet which reduces fatty acid outflux in the liver. It is necessary to further identify detailed molecular mechanisms on how GDS regulates hepatic lipid disposal in the liver and how inhibition of HTR2A signaling reduces hepatic TG accumulation. In addition, as the mortality increases geometrically with the increasing levels of fibrosis in NAFLD patients and many of genes involved in proinflammatory and profibrogenic pathways are downregulated in Htr2a LKO mice, it would be of interest to test whether HTR2A antagonism can effectively stop the progression of hepatic steatosis to fibrosis in the future However, as sarpogrelate shows rare hepatotoxicity in real world practice, this concern might not be a problem to use it as an anti-NAFLD drug.
Crane et al. Oh et al. In the present study, we demonstrated that HFD-fed Tph1 GKO mice are protected against hepatic steatosis without affecting systemic energy homeostasis. These findings suggest that there may be more various functions of 5-HT in different tissues. Thus, a more detailed study of the different roles of 5-HT using tissue-specific KO strategy will broaden our understanding of the function of this ancient neurotransmitter.
A third loxP site is inserted downstream of exon 3 of the Htr2a gene. The germ line transmissions of the F1 mice were analyzed and the confirmed offspring were crossed with transgenic flippase mice to remove the flanking FRT sites, resulting in Htr2a -floxed mice. All animal experiments were complied with relevant ethical regulations. Experimental protocols for this study were approved by the institutional animal care and use committee at the Korea Advanced Institute of Science and Technology.
Heat production was calculated as 3. For the insulin tolerance test, 0. Enzymatic colorimetric assay kits for total cholesterol Roche, Basel, Switzerland , high-density lipoprotein cholesterol Roche , triglyceride Roche , and free fatty acid Wako, Osaka, Japan were used to determine plasma levels on a Cobas modular analyzer Roche at GreenCross LabCell. To measure mouse platelet poor plasma PPP serotonin, blood samples were collected by retro-orbital bleeding or sampling from the portal vein.
Serotonin levels in tissue lysates were determined with an enzyme-linked immunosorbent assay kit IBL International or liquid chromatography-mass spectrometry method. Gene expression was relatively quantified based on the delta delta Ct threshold cycle method with the beta-actin gene as a reference gene.
The sequences of primers are given in Supplementary Table 1. For quantitative evaluation of hepatic steatosis, NAS, which consists of steatosis, lobular inflammation, and ballooning, was used. NAS was determined by a single certified pathologist, blinded for other information. All experiments using human participant blood samples were complied with relevant ethical regulations. After previous approval by the institutional review board of Severance Hospital , and written, informed consent by all subjects, 9 living donors for liver transplantation were included in this study.
Clinical data are given in Supplementary table 2. Body weight and height were measured using a digital scale, and body mass index was calculated by dividing weight kg by the square of height m 2. Laboratory parameters including complete blood count and differential count, calcium, phosphorus, glucose, blood urea nitrogen, creatinine Cr , uric acid, cholesterol, total protein, albumin, alkaline phosphatase, aspartate transferase, ALT, total bilirubin, gamma-GTP, TG, high-density lipoprotein HDL cholesterol, low-density lipoprotein LDL cholesterol, sodium, potassium, chloride, prothrombin time, and activated prothrombin time were measured within 4 weeks before living donor hepatectomy.
Transient elastography was performed using the liver Fibroscan Echosens, Paris, France. Donor hepatectomy was performed according to standardized procedures. Blood samples for serotonin measurements were drawn simultaneously from the portal vein and peripheral veins during operation. HTseq v0. P values below 0. Further information on research design is available in the Nature Research Reporting Summary linked to this article. The data that support the findings of this study are available from the authors on reasonable request.
The originally published version of this Article contained an error in Figure 2. Younossi, Z. Article Google Scholar. Pais, R. NAFLD and liver transplantation: current burden and expected challenges. Michelotti, G. Promrat, K. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
Hepatology 51 , — Sullivan, S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology 55 , — Chalasani, N. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
Gastroenterology , — Oh, H. Non-alcoholic fatty liver diseases: update on the challenge of diagnosis and treatment. Walther, D. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science , 76 Zhang, X. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science , Keszthelyi, D. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function.
Matthes, S. Peripheral serotonin synthesis as a new drug target. Trends Pharmacol. Berger, M. The expanded biology of serotonin. El-Merahbi, R. The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett.
Richter, G. Release of tryptophan and serotonin into the portal vein of the isolated perfused rat small intestine. Deacon, A. The measurement of 5-hydroxyindoleacetic acid in urine. Crane, J. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.
Oh, C. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Kim, H. Serotonin regulates pancreatic beta cell mass during pregnancy. Yadav, V. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell , — Lesurtel, M. Platelet-derived serotonin mediates liver regeneration.
Science , — Sumara, G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. Osawa, Y. L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin. Namkung, J. Inhibition of serotonin synthesis induces negative hepatic lipid balance.
Diabetes Metab. Young, R. Augmented capacity for peripheral serotonin release in human obesity. Westerbacka, J. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 47 , — Tomizawa, M. Triglyceride is strongly associated with nonalcoholic fatty liver disease among markers of hyperlipidemia and diabetes. Karlas, T. Individual patient data meta-analysis of controlled attenuation parameter CAP technology for assessing steatosis.
Kleiner, D. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Liver Dis. Musso, G. Lipid Res. Anstee, Q. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Crespo, J. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34 , — Wieckowska, A. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Cai, D.
Ribeiro, P. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Rolo, A. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Ye, D. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61 , — Miura, K.
Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57 , — Hennig, E. Extracellular matrix and cytochrome P gene expression can distinguish steatohepatitis from steatosis in mice.
Cell Mol. Notably, it is becoming increasingly clear that these death signals do not always result in cell death. These incomplete apoptotic signals are initiated in hepatocytes, affecting stellate cells and macrophages [ 11 , 12 , 13 ].
These new findings suggest potential novel targets to treat NASH. This review focuses on recent advances on lethal and sublethal hepatocyte death signals and the role they may play in the pathogenesis of NASH. In this review, lipotoxicity refers to toxicity caused by the presence of excessive free fatty acids FFAs and their metabolites in the cells; based on the most recent findings, it includes both sublethal and lethal effects [ 10 , 14 ].
Long-chain fatty acids, i. Optimal amounts of FFAs, released mainly from subcutaneous fat by lipolysis [ 15 ], are required for membrane composition and as a source of energy. However, obesity and insulin resistance trigger adipocytes to release increased levels of circulating FFAs into the bloodstream, which then enter hepatocytes [ 15 ].
To protect themselves against lipotoxicity, hepatocytes typically induce steatosis, storing the increased amounts of FFAs as non-toxic triglycerides TGs [ 16 , 17 ]. However, when hepatic FFAs exceed the storage limit, they activate hepatocyte death signaling [ 18 ].
Saturated FFAs are frequently found in animal fats and are toxic to hepatocytes. Accordingly, saturated FFAs reduce membrane fluidity by making the membrane more rigid [ 19 ] and present a poor conversion into TG-enriched lipid droplets.
The most common saturated FFA found in humans is palmitic acid Unsaturated FFAs, such as oleic acid , abundant in olive oil and palmitoleic acid , abundant in macadamia nuts [ 20 ], are less toxic. Unsaturated FFAs are generally present in liquid form at biological temperatures because of their low melting temperatures and exhibit low toxicity when cultured with hepatocytes. The latter is likely due to their incorporation into TGs and the increased stability of lipid droplets containing a higher percentage of unsaturated acyl chains [ 16 ].
Although this review mainly focuses on free fatty acid-mediated lipotoxic pathways, lysophosphatidylcholine LPC , a lipid metabolite of palmitic acid, is also cytotoxic [ 24 ]. Increased hepatic synthesis and dysregulation of cholesterol metabolism are associated with severity of NAFLD [ 25 ].
Furthermore, free cholesterol is cytotoxic, triggering hepatocyte apoptosis [ 26 ]. In addition to lipid metabolites, gut-derived bacterial endotoxins such as lipopolysaccharide LPS have been described as crucial cofactors in the pathogenesis of liver injury in NASH. Low doses of LPS are thought to attract neutrophil migration, further promoting hepatocyte apoptosis via the strong pro-death activity of non-parenchymal cells, especially lysosomal enzyme myeloperoxidase MPO -containing neutrophils [ 28 ].
Caspases are a family of cysteine-proteases that execute the final phase of apoptosis. Mammalian caspases 2, 3, 7, 8, 9, and 10 are defined as apoptotic caspases, whereas caspases 1, 4, 5, 11, and 12 are associated with inflammation [ 29 ]. Caspase 3 is an indispensable caspase for chromatin condensation and DNA fragmentation, which are the final steps of apoptosis Fig. As several studies have indicated caspase involvement in NASH pathogenesis, caspase inhibitors have garnered major clinical interest for the possible treatment of the disease.
Several studies have suggested that pan-caspase inhibitors, including IDN Emricasan and VX, can effectively suppress apoptosis, inflammation, and fibrosis, both in vitro and in animal models [ 32 , 33 ]. In addition to broad-range caspase inhibitors, it has recently been reported that specific depletion of caspase 3 protects against NASH, suggesting that targeting specific caspases is a viable approach [ 34 ].
In this particular study, caspase 3 knockout mice displayed reduced hepatocyte apoptosis and hepatic collagen deposition when fed a methionine-choline-deficient MCD diet. Free fatty acids FFAs induce aggregation of DR5 on the cell membrane and activate caspase following the formation of a complex with DR5.
Caspase 8 activation results in cleavage of BH3-only protein Bid to truncated t -Bid, thereby contributing to mitochondrial dysfunction and cell death. Degradation of cIAP, an anti-apoptotic protein, also contributes to lipoapoptosis. Caspase 8 CASP8 is an initiator caspase required for extrinsic death receptor-mediated apoptosis and is crucial for FFA-mediated apoptosis in hepatocytes Fig.
Recently, Hatting et al. Interestingly, although alcoholic liver diseases and NASH share similar clinical and pathological manifestations, caspase 8 inhibition does not seem to protect mice from ethanol-induced apoptosis and actually enhances caspase 9 CASP9 -dependent intrinsic mitochondrial cell death by inducing release of cytochrome c [ 38 ]. In addition, GS is a caspase inhibitor with selective activity against caspases 1, 8, and 9, but not caspase 3.
In this study, significant decreases in alanine aminotransferase ALT and CK fragments were observed in patients with NASH, suggesting that pharmacological caspase inhibitors targeting upstream death signals could also reduce hepatocyte apoptosis in NASH and might offer a valuable therapeutic strategy. Caspase 9 is an essential initiator caspase that executes the mitochondrial pathway of apoptosis [ 40 ].
Interestingly, the ballooned hepatocyte phenotype that is a pathological feature of NASH is characterized by reduced expression of caspase 9 [ 12 ]. This is thought to be an escape mechanism from apoptosis in FA-stressed hepatocytes, as it prevents ballooned hepatocytes exposed to death signals from dying [ 12 ].
Furthermore, these cells were shown to initiate pro-fibrotic signaling through the Hedgehog signaling pathway, suggesting that ballooned hepatocytes are not solely the result of NASH but might also contribute to the development of inflammation and fibrosis [ 12 ]. Caspase 2 CASP2 is an initiator caspase activated by various intracellular stresses and toxic agents, including saturated FFAs [ 29 , 41 , 42 ].
Caspase 2 was originally recognized as a mediator of mitochondrial dysfunction, promoting cytochrome c release from mitochondria into the cytosol Fig. Recent studies by Machado et al. Furthermore, caspase 2 inhibition also decreased lipotoxicity-induced Hedgehog signaling, a known mediator of fibrotic activity, as well as fibrosis [ 9 ]. Caspase 2 depletion also seems to alter the metabolic state of mice via an undefined mechanism, preventing insulin resistance and obesity [ 44 , 45 ].
As caspase 2 deletion in mice caused no significant phenotype changes in the experiments of Machado et al. However, caution is advised as a tumor-suppressive role for caspase 2 has been suggested and caspase inhibition might contribute to genomic instability and carcinogenesis in the long term [ 46 , 47 ].
Taken together, both clinical and experimental data suggest that caspases are attractive candidates for the treatment of NASH. In particular, inhibition of specific caspases may enable therapeutics to focus on the disease target and reduce adverse effects. Interestingly, it has recently been shown that sublethal amounts of caspase 3, induced by FFAs, can lead to the release of pro-inflammatory vesicles from hepatocyte membranes, which can activate macrophages and may exacerbate inflammation [ 11 , 48 ].
These important findings show that caspase inhibitors not only improve NASH by decreasing cell death but can also decrease inflammation when apoptosis is incomplete. Hepatocyte lipoapoptosis is often triggered by death receptors DRs on the plasma membrane Fig. In some cells, such as lymphocytes, DR activation can directly activate caspase 3.
However, in hepatocytes, DR signaling requires amplification through the intrinsic mitochondrial pathway, which then leads to caspase 3 activation and cell death Fig. DR5 in particular appears to play a major role in FFA-induced hepatocyte death [ 36 ]. After stimulation by FFA, DR5 undergoes self-aggregation on the plasma membrane and activates caspase 8. Interestingly, DR5 up-regulation by FFAs not only induces cell death, but also contributes to the release of hepatocyte-derived extracellular vesicles EVs responsible for intercellular communication [ 53 ].
Such vesicles are increasingly being recognized as potential factors in the pathogenesis of NASH [ 13 , 48 , 54 , 55 ]. These findings support the existing non-canonical role for TRAIL as a pro-inflammatory mediator [ 57 ]. Notably, the Rho-kinase ROCK inhibitor fasudil hydrochloride hydrate Fasudil is frequently used in Japan to treat subarachnoid hemorrhage and prevent cerebral vasospasm and subsequent ischemic injury [ 59 ].
In addition, several JNK inhibitors have already been tested in clinical trials for other diseases, including idiopathic pulmonary fibrosis and inflammatory endometriosis [ 60 ]. Lipotoxicity in hepatocytes and cholangiocytes. MiRa also contributes to lipoapoptosis. Although saturated free fatty acids FFAs are poorly incorporated into lipid droplets, steatosis occurs to some extent in hepatocytes. In contrast, FFAs do not induce steatosis in cholangiocytes.
JNK does not contribute to cell death in cholangiocytes. This discovery was somewhat surprising as CFLAR is a well-known negative regulator of above-mentioned receptor signaling [ 35 ]. Hepatocyte-specific Cflar knockout in HFD-fed mice promoted increased body and liver weights and led to a more severe version of NASH that included inflammatory changes in the liver.
Autophagy is an intracellular pathway responsible for the turnover of unwanted proteins or organelles [ 69 , 70 ] and it can also regulate intracellular lipid levels by removing lipid droplets through a process termed lipophagy [ 71 ]. Although autophagy serves as a quality control mechanism for organelles and proteins, dysregulation of autophagy can promote cell death [ 72 ]. Dysregulation of autophagic function has also been reported to promote the development of NASH and contribute to hepatocyte lipoapoptosis [ 73 ].
The current understanding is that although FFAs can induce initiation of autophagy, they inhibit autophagic flux, defined by the rate of autophagic degradation [ 74 ]. Palmitic acid-induced inhibition of autophagic flux results in the accumulation of p62, an increase in the microtubule-associated protein 2 light chain 3 LC3-II :LC3-I ratio, and accumulation of autophagosomes [ 73 ]. Pharmacological promotion of autophagic activity by carbamazepine and rapamycin has also been shown to improve a murine model of NASH [ 75 ].
However, this finding raises the question as to how FFAs impair autophagic flux. To this end, a recent study demonstrated that palmitic acid impaired autophagy flux by preventing the late stages of autophagy. Miyagawa et al. Impairment of autophagic flux induced the accumulation of autophagosomes in palmitic acid-treated but not oleic acid-treated cells. In addition, Tanaka et al.
Rubicon is post-transcriptionally up-regulated by palmitic acid, suppressing the late stages of autophagy. Inhibition of rubicon by RNAi restored palmitic acid-induced autophagy impairment as shown by reduction of p62 and LC-II, which lead to reduced apoptosis In addition, mice with hepatocyte-specific rubicon knockout displayed improvements in liver steatosis and injury and restored autophagic function. Rubicon deficiency was shown to inhibit JNK signaling both in vitro and in vivo.
Accordingly, this protein may serve as a key mediator of the two major death pathways during lipotoxicity, and targeting it may contribute to the treatment of NASH. Interestingly, JNK may activate p62 via an as-yet undefined mechanism in leukemia cells [ 78 ]; it should thus be determined whether, conversely, JNK-induced signals could alter autophagy in NASH. Therefore, one potentially beneficial option may be to replace a portion of the saturated FFAs in a diet with medium-chain fatty acid-containing products, such as coconut oil.
The ER plays an essential role in homeostasis by regulating cellular protein folding and assembly. Disruption of ER homeostatic mechanisms by toxic reagents or nutrient excess induces the accumulation of misfolded or unfolded proteins within the organelle. During the UPR, these sensors are released from the intraluminal chaperone glucose-regulated protein 78 GRP78 [ 81 , 82 , 83 ].
The UPR initially transmits signals throughout the cell to inhibit protein synthesis and increase the capacity of the ER. However, when stress overwhelms ER capacity, the pathway shifts to transmitting pro-death signals, inducing apoptosis Fig. Several studies have also examined the mechanisms of saturated FFA-induced ER stress and cell death [ 61 , 87 , 88 , 89 ]. Endoplasmic reticulum ER stress-mediated apoptosis. Maresin 1 MAR1 resolves lipotoxicity and ER stress by up-regulating UPR pro-survival mechanisms and preventing the excessive stimulation of pro-apoptotic pathways.
MAR1 is also able to attenuate ER stress in macrophages, restoring Kupffer cell phagocytic capacity to clear apoptotic hepatocytes. Recent ER stress-related research has shed light on some newly determined mediators of active cell recovery from stress, despite the previous belief that healing from stress after injury was a passive event [ 91 ].
Maresin 1 MAR1 is one of the various specialized pro-resolving lipid mediators that has been found to actively facilitate the return of injured tissue to homeostasis [ 91 ]. Rius et al. In addition, MAR1 increased phagocytosis in Kupffer cells, promoting the clearance of apoptotic hepatocytes.
Because MAR1 was isolated as a pro-resolving mediator whose activity is promoted by omega-3 essential FAs, this study potentially explains how polyunsaturated FFAs exert their positive effects on obesity-related diseases. It also suggests the possibility of efficiently applying specific polyunsaturated FFA-derived mediators beneficial to patients with NASH. Current data suggest that ER stress and autophagy are not independent phenomena but are interconnected.
For example, autophagy is induced to dispose of misfolded proteins remaining after ER-associated protein degradation [ 93 ]. Recently, Willy et al. Mitochondria are also a target of FFA assault. Excessive production of ROS is believed to induce oxidative stress, leading to further impairment of mitochondrial respiration.
However, above a threshold of palmitic acid, mitochondrial respiration becomes gradually impaired, followed by release of cytochrome c to the cytosol leading to apoptosis [ 90 , 97 , 98 ]. Butylated hydroxyanisole BHA , an antioxidant, counteracts lipotoxicity in cultured rat hepatocytes [ 97 ] and vitamin E has been shown to be superior to a placebo for the treatment of biopsy-proven NASH in human adults without type 2 diabetes [ 99 ].
Regarding recent developments in ROS-related research, interesting interactions between JNK and mitochondrial respiration have been reported [ 97 ]. Interaction of JNK with Sab, an outer membrane mitochondrial protein, leads to inhibition of mitochondrial respiration during palmitic acid treatment and increased ROS release, thus contributing to cell death in cultured hepatocytes Fig.
Sab knockdown significantly inhibited palmitic acid-induced cell death in cultured hepatocytes. Interestingly, this effect occurred only at the late stage of apoptosis, suggesting that Sab-related JNK activity contributed to cell death via gradual impairment of mitochondrial dysfunction. This study suggested a sensitization toward the mitochondrial pathway of apoptosis even in early phases of NAFLD. Epigenetic changes are defined as chemical modifications of genomic DNA that are unrelated to alteration of the primary DNA sequence.
They include DNA methylation, altered expression of non-coding RNAs, histone modification, and chromatin remodeling [ , ]. Epigenetic changes can be reversed by interventional approaches [ ], raising clinical interest in this area [ , , ]. This chapter will mainly focus on non-coding RNAs, the most intensively investigated form of epigenetic machinery and the one most related to hepatocyte death signaling [ ].
Non-coding RNAs do not encode proteins, but function as cellular signaling modulators that regulate gene expression as well as protein translation. For example, miRa, miRb, miRc, miRa, miRb, and miR were shown to be up-regulated during FFA acid-treated human heoatpcytes as well as in high-fat diet-fed mice model [ ].
In human liver biopsy, dozens of miRNAs were found to be differentially expressed in NASH compared to normal controls [ ], including mir and mi In terms of hepatic lipotoxicity, targeting these miRNAs could potentially decrease the amount of FFAs in hepatocytes which, in turn, might reduce the risk of hepatocyte apoptosis.
Thus, miR may serve as a candidate marker for disease severity [ ]. Recently, miRa has emerged as a key regulator of hepatic lipid homeostasis and has gained attention because of its significance in metabolic diseases [ , , , , ]. MiRa levels were reportedly up-regulated in steatotic hepatocytes as well as in liver tissues of HFD-fed mice, and are associated with disease severity in the liver of human NAFLD patients [ , ].
Overexpression of miRa has been shown to increase lipid accumulation as well as FFA-induced apoptosis in cultured primary rat hepatocytes Fig. Cholestatic presentation of NASH has been suggested to develop in a subset of patients [ ] and FFAs induce apoptosis not only in hepatocytes but also in cholangiocytes.
Indeed, cholangiocyte lipoapoptosis has been shown to occur in high fat-high sucrose-fed mice [ , ]. Natarajan et al. Foxo3a has also been found to promote expression of the pro-apoptotic BH3 protein PUMA, which has been shown to trigger apoptosis in cholangiocytes Fig. Another difference of palmitate-induced change between cholangiocytes and hepatocytes is steatosis.
Although palmitic acid is poorly incorporated into lipid droplets, steatosis occurs to some extent in hepatocytes. In contrast, saturated free fatty acids do not seem to induce steatosis in cholangiocytes. These differences might result from different expression of proteins that modulate lipid synthesis, liphophagy, and lipolysis: however, further studies are required.
Miyamoto et al. They noted that decrease of miRp was induced by ER stress, but was independent of eiF2alpha phosphorylation. Thus, their results suggested that up-regulation of miRp could be a novel approach to treat NASH. One of the most profound discoveries was by Atanasovska et al. In addition, knockdown of lnc18q The authors could not detect any apoptosis or an increase of biochemical markers such as cleaved PARP, which suggested caspase 3-independent hepatocyte death.
Nevertheless, apoptosis in these knockdown cells could not be entirely ruled out, as 18q The study of non-coding RNAs has thus provided new insights into the regulation of hepatocyte viability in NASH and widens the possibility of intervention. Although apoptosis is the fundamental process by which organized cell death occurs, caspase inhibition does not completely inhibit hepatocyte cell death in NASH [ 32 ].
This has led researchers to consider other types of cell death [ , , ]. Treatment with palmitic acid induces not only apoptosis, but also an emerging type of cell death termed necroptosis [ , ]. Although categorized as a form of programmed cell death, necroptosis does not utilize caspases but rather receptor-interacting proteins RIP 1 and 3 and the phosphorylation of mixed lineage kinase domain-like MLKL proteins [ , ].
Necroptosis may, therefore, serve as a backup pathway to enable cell death when apoptosis is inhibited and vice versa. However, recent functional studies with RIP3 knockout mice have provided controversial results. Although both diets induce similar pathological features, their pathogenic mechanisms are quite distinct. Further studies employing other mediators of necroptosis, such as MLKL, should ideally be performed to explore this concept. Finally, new forms of cell death, such as ferroptosis the iron-dependent accumulation of lipid hydroperoxides [ ] and pyroptosis another inflammatory form of programmed cell death mediated by human caspases 1, 4 and 5 [ ], have been recently described in other diseases.
However, the role of these new types of cell death in NASH remains unclear and will again require further investigation. These pathways form a signaling network Fig. Recent advances suggest that even when apoptosis is incomplete, FFA-induced cell death signals are harmful for the progression of NASH. This is due to the induction of pro-inflammatory and pro-fibrotic signals to neighboring parenchymal cells.
Targeting of apoptotic signaling may, therefore, inhibit hepatocyte cell death, as well as inflammation, in NASH patients. Interactions between lethal and nonlethal pro-inflammatory signaling by saturated free fatty acids FFAs and potential interventions for NASH. These signals ultimately merge to induce mitochondrial dysfunction and the release of the executioner caspase 3, leading to cell death.
Sublethal amounts of FFAs induce pro-inflammatory signaling in parenchymal cells, leading to inflammation and fibrosis. Based on recent discoveries regarding pathways involved in FFA-induced toxicity, the proteins and drugs highlighted in green are potential interventional targets for NASH. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
PubMed Article Google Scholar. Prevalence of nonalcoholic steatohepatitis in Japanese patients with morbid obesity undergoing bariatric surgery. J Gastroenterol. Epidemiological survey and risk factor analysis of fatty liver disease of adult residents, Beijing, China. J Gastroenterol Hepatol. PubMed Google Scholar. Hepatocarcinogenesis in non-alcoholic fatty liver disease in Japan.
The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Decoding cell death signals in liver inflammation. J Hepatol. Cytokeratin fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study.
Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res. Extracellular vesicles in liver pathobiology: small particles with big impact. Mixed lineage kinase 3 mediates release of C-X-C motif ligand bearing chemotactic extracellular vesicles from lipotoxic hepatocytes.
Google Scholar. Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. Triglyceride accumulation protects against fatty acid-induced lipotoxicity.
Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. Fatty acid profile, tocopherol, squalene and phytosterol content of walnuts, almonds, peanuts, hazelnuts and the macadamia nut.
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