37, 47, 48 The expression level of IL-17 strongly correlates with the degree of fibrosis in patients with hepatitis B virus (HBV)-related chronic liver diseases.47 IL-17A-activated fibroblasts enhances

production of IL-6 in one of the mouse models.49 In addition, IL-17A independently induces the activation of collagen-producing cells contributing to BDL- or CCL4-induced liver fibrosis in mice. Thus, it is likely that Th17 and IL-6 also play a role in p35−/− liver fibrosis. Of note, IL-22 has recently been shown to be primarily synthesized by the Th17, Th22, γδT, NK, and NKT cell lineages.39 A weakness of the study herein is the failure to study the mechanism of amplified fibrinogenesis in these mice. Our initial efforts were placed on defining the specific roles of the p35 versus p40 subunits in modulating the inflammatory disease we previously reported in dnTGFβRII mice. CP-868596 Hence, the appearance of fibrosis was unexpected and must become a subject of future studies.

We note the role of IL-22 in tissue fibrosis remains unclear or controversial50, 51 and suggest that the fibrosis in p35−/− mice is most likely due to a reduction Pexidartinib mouse in IFN-γ and the increase in IL-17. Future directions will focus on the generation of IL-17, p35 double knockout mice as a model to explore these issues including fibrinogenesis and cytokine interactions with hepatic stellate cells. Interestingly, Th17 cells have been classified as an independent T-helper cell subset through the identification of their differentiation factors IL-6 and TGFβ1.52 Recent studies demonstrate that Th17 cells can also be induced without TGFβ1 but by way of the effects of IL-6, IL-1β, and IL23. These “alternative” Th17 cells are thought to be more pathogenic than the “classical”

Th17 cells.53 Because the TGFβ pathway is disrupted in the dnTGFβRII mice, the Th17 cells in the IL-12p35−/−dnTGFβRII are likely to be the “alternative” type with elevated pathogenic character. In summary, our results reveal distinct phenotypes in terms of fibrosis, liver inflammation, and cytokine profile among the dnTGFβRII strain and its two derivative strains, IL-12p35−/− and IL-12p40−/− mice. Importantly, because the deletion of p35 gene disrupts IL-12 and IL-23, whereas deletion of p40 gene disrupts IL-12 and IL-35, the different phenotypes Methamphetamine of 12p35−/− and 12p40−/− reflect the differential effects of a proinflammatory cytokine, IL-23, versus a presumably inhibitory cytokine, IL-35, in the absence of IL-12 and a functional TGFβ pathway. In particular, our results suggest a potential role of IL-35 in protection against development of fibrosis. Further investigation of the IL-12 family members, especially the poorly studied IL-35, should shed more light on the immunopathogenic mechanism of the PBC-like liver disease in the dnTGFβRII mice, especially pathogenesis of liver fibrosis.

37, 47, 48 The expression level of IL-17 strongly correlates with the degree of fibrosis in patients with hepatitis B virus (HBV)-related chronic liver diseases.47 IL-17A-activated fibroblasts enhances

production of IL-6 in one of the mouse models.49 In addition, IL-17A independently induces the activation of collagen-producing cells contributing to BDL- or CCL4-induced liver fibrosis in mice. Thus, it is likely that Th17 and IL-6 also play a role in p35−/− liver fibrosis. Of note, IL-22 has recently been shown to be primarily synthesized by the Th17, Th22, γδT, NK, and NKT cell lineages.39 A weakness of the study herein is the failure to study the mechanism of amplified fibrinogenesis in these mice. Our initial efforts were placed on defining the specific roles of the p35 versus p40 subunits in modulating the inflammatory disease we previously reported in dnTGFβRII mice. Erlotinib in vivo Hence, the appearance of fibrosis was unexpected and must become a subject of future studies.

We note the role of IL-22 in tissue fibrosis remains unclear or controversial50, 51 and suggest that the fibrosis in p35−/− mice is most likely due to a reduction Ceritinib cost in IFN-γ and the increase in IL-17. Future directions will focus on the generation of IL-17, p35 double knockout mice as a model to explore these issues including fibrinogenesis and cytokine interactions with hepatic stellate cells. Interestingly, Th17 cells have been classified as an independent T-helper cell subset through the identification of their differentiation factors IL-6 and TGFβ1.52 Recent studies demonstrate that Th17 cells can also be induced without TGFβ1 but by way of the effects of IL-6, IL-1β, and IL23. These “alternative” Th17 cells are thought to be more pathogenic than the “classical”

Th17 cells.53 Because the TGFβ pathway is disrupted in the dnTGFβRII mice, the Th17 cells in the IL-12p35−/−dnTGFβRII are likely to be the “alternative” type with elevated pathogenic character. In summary, our results reveal distinct phenotypes in terms of fibrosis, liver inflammation, and cytokine profile among the dnTGFβRII strain and its two derivative strains, IL-12p35−/− and IL-12p40−/− mice. Importantly, because the deletion of p35 gene disrupts IL-12 and IL-23, whereas deletion of p40 gene disrupts IL-12 and IL-35, the different phenotypes HDAC inhibitor of 12p35−/− and 12p40−/− reflect the differential effects of a proinflammatory cytokine, IL-23, versus a presumably inhibitory cytokine, IL-35, in the absence of IL-12 and a functional TGFβ pathway. In particular, our results suggest a potential role of IL-35 in protection against development of fibrosis. Further investigation of the IL-12 family members, especially the poorly studied IL-35, should shed more light on the immunopathogenic mechanism of the PBC-like liver disease in the dnTGFβRII mice, especially pathogenesis of liver fibrosis.

Sample collection was approved by the Institutional Review Board of the corresponding institutes and recorded by the National Institutes of Health (NIH) Office of Human Subjects Research. BTK inhibitor A total of 23 ICC and CHC cases were used to build mRNA and microRNA signatures. The initial diagnosis was made based on serological test and imaging, and was confirmed histopathologically by pathologists. The characteristics of 68 Caucasian ICC patients from an independent cohort were described recently.23 HuCCT1 and HUH28 cell lines were used

for miR-200c functional studies. These cell lines were obtained from the Japanese Collection of Research Bioresources Cell Bank and were cultured in RPMI supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL streptomycin, and 2 mmol/L L-glutamine. An immortalized human cholangiocyte-derived cell line, H69, kindly provided by Dr. Gregory Gores (Mayo Clinic), was cultured as described.24 A Protein Tyrosine Kinase inhibitor luciferase reporter

containing an upstream 0.9-kb fragment of pri-miR-200c was kindly provided by Dr. Li Wang (University of Utah School of Medicine).25 A detailed description of other transfection reagents, methodologies such as cell culture, cell proliferation and apoptosis assays, luciferase assay, immunohistochemical analysis, and cell migration and invasion assays can be found in the Supporting Materials. Total RNA was extracted from frozen tissue using Trizol (Invitrogen) according to the manufacturer’s protocol. Only RNA samples with good RNA quality as confirmed with the Agilent 2100 Bioanalyzer (Agilent Technologies) were

included for array study. Gene expression profiling of 23 tumor samples (16 ICC, 7 CHC), as well as seven paired noncancerous liver tissues from ICC patients and seven benign liver lesions (five focal nodular hyperplasia [FNH], two adenoma) was carried out on Affymetrix GeneChip Human Gene-ST 1.0 arrays according to the manufacturer’s protocol and processed as described.26 Affymetrix gene expression arrays obtained from different platforms were combined Ureohydrolase with the match probes package in R. Raw gene expression data were normalized using the robust multi-array average (RMA) method and global median centering. For genes with more than one probe set, the mean gene expression was calculated. Total RNA was used for the nCounter microRNA platform. All sample preparation and hybridization was performed according to the manufacturer’s instructions. All hybridization reactions were incubated at 65°C for a minimum of 12 hours. Hybridized probes were purified and counted on the nCounter Prep Station and Digital Analyzer (NanoString) following the manufacturer’s instructions. For each assay a high-density scan was performed.

Sample collection was approved by the Institutional Review Board of the corresponding institutes and recorded by the National Institutes of Health (NIH) Office of Human Subjects Research. Selleck AZD4547 A total of 23 ICC and CHC cases were used to build mRNA and microRNA signatures. The initial diagnosis was made based on serological test and imaging, and was confirmed histopathologically by pathologists. The characteristics of 68 Caucasian ICC patients from an independent cohort were described recently.23 HuCCT1 and HUH28 cell lines were used

for miR-200c functional studies. These cell lines were obtained from the Japanese Collection of Research Bioresources Cell Bank and were cultured in RPMI supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL streptomycin, and 2 mmol/L L-glutamine. An immortalized human cholangiocyte-derived cell line, H69, kindly provided by Dr. Gregory Gores (Mayo Clinic), was cultured as described.24 A AZD2014 luciferase reporter

containing an upstream 0.9-kb fragment of pri-miR-200c was kindly provided by Dr. Li Wang (University of Utah School of Medicine).25 A detailed description of other transfection reagents, methodologies such as cell culture, cell proliferation and apoptosis assays, luciferase assay, immunohistochemical analysis, and cell migration and invasion assays can be found in the Supporting Materials. Total RNA was extracted from frozen tissue using Trizol (Invitrogen) according to the manufacturer’s protocol. Only RNA samples with good RNA quality as confirmed with the Agilent 2100 Bioanalyzer (Agilent Technologies) were

included for array study. Gene expression profiling of 23 tumor samples (16 ICC, 7 CHC), as well as seven paired noncancerous liver tissues from ICC patients and seven benign liver lesions (five focal nodular hyperplasia [FNH], two adenoma) was carried out on Affymetrix GeneChip Human Gene-ST 1.0 arrays according to the manufacturer’s protocol and processed as described.26 Affymetrix gene expression arrays obtained from different platforms were combined check details with the match probes package in R. Raw gene expression data were normalized using the robust multi-array average (RMA) method and global median centering. For genes with more than one probe set, the mean gene expression was calculated. Total RNA was used for the nCounter microRNA platform. All sample preparation and hybridization was performed according to the manufacturer’s instructions. All hybridization reactions were incubated at 65°C for a minimum of 12 hours. Hybridized probes were purified and counted on the nCounter Prep Station and Digital Analyzer (NanoString) following the manufacturer’s instructions. For each assay a high-density scan was performed.

In the last 20 years, our understanding of the needs of women with bleeding disorders has increased and our ability to manage their needs has improved. It is now well-established that heavy menstrual bleeding, or menorrhagia, is the most common symptom that women with bleeding disorders experience. Over the last 20 years, data have been published about the prevalence of menorrhagia in women with bleeding disorders. These data are summarized in Table 1. It has been well-established that menorrhagia is more prevalent among women with bleeding disorders. In the last 13 years, it has

also been established that bleeding disorders are more prevalent among women with menorrhagia. Among women with menorrhagia, the prevalence of von Willebrand disease (VWD) has been reported to be 5–20% [1–7] with an overall estimate of 13% [8] based on a systematic review. The prevalence of VWD and other bleeding Saracatinib mouse disorders in women with menorrhagia is summarized in Table 2. There are limited data regarding the prevalence of bleeding disorders among adolescents with menorrhagia, but in the last 8 years, it has become apparent that they are at least as likely to have an underlying

bleeding disorder as adult women with heavy menstrual bleeding. The prevalence of bleeding disorders in adolescents with menorrhagia (from studies of inpatients, outpatients and patients referred to a haemophilia Dipeptidyl peptidase treatment centre) are summarized in Table 3. Menorrhagia is defined as heavy menstrual bleeding that lasts for more than 7 days [9] or results in the loss of more than 80 mL of blood per mTOR inhibitor menstrual cycle [9]. As measuring actual menstrual blood

loss is not feasible in clinical practice, Higham et al. devised a pictorial blood assessment chart (PBAC) as an alternative [10]. In the investigators’ original study, women compared the degree of saturation of their pads and tampons with those depicted on a chart. Lightly stained pads or tampons obtained a score of 1, moderately stained pads or tampons a score of 5, and soaked pads or tampons a score of 20. The scores were summed and a total score of greater than 100 per cycle was associated with a menstrual blood loss of greater than 80 mL. A drawback of the use of the chart is that it must be completed prospectively and its results are not available at the time of an initial evaluation. Additionally, the validity of the chart remains uncertain [11,12]. Nonetheless, in the last 5 years, the PBAC has been used successfully to monitor response to treatment in studies of women with bleeding disorders [13,14]. In most situations, however, the practitioner must rely on a menstrual history and clinical impression to decide whether a woman has menorrhagia. Warner et al. attempted to assess the volume of blood loss by means of specific clinical features.

In the last 20 years, our understanding of the needs of women with bleeding disorders has increased and our ability to manage their needs has improved. It is now well-established that heavy menstrual bleeding, or menorrhagia, is the most common symptom that women with bleeding disorders experience. Over the last 20 years, data have been published about the prevalence of menorrhagia in women with bleeding disorders. These data are summarized in Table 1. It has been well-established that menorrhagia is more prevalent among women with bleeding disorders. In the last 13 years, it has

also been established that bleeding disorders are more prevalent among women with menorrhagia. Among women with menorrhagia, the prevalence of von Willebrand disease (VWD) has been reported to be 5–20% [1–7] with an overall estimate of 13% [8] based on a systematic review. The prevalence of VWD and other bleeding SCH 900776 mw disorders in women with menorrhagia is summarized in Table 2. There are limited data regarding the prevalence of bleeding disorders among adolescents with menorrhagia, but in the last 8 years, it has become apparent that they are at least as likely to have an underlying

bleeding disorder as adult women with heavy menstrual bleeding. The prevalence of bleeding disorders in adolescents with menorrhagia (from studies of inpatients, outpatients and patients referred to a haemophilia Thymidylate synthase treatment centre) are summarized in Table 3. Menorrhagia is defined as heavy menstrual bleeding that lasts for more than 7 days [9] or results in the loss of more than 80 mL of blood per GW-572016 mouse menstrual cycle [9]. As measuring actual menstrual blood

loss is not feasible in clinical practice, Higham et al. devised a pictorial blood assessment chart (PBAC) as an alternative [10]. In the investigators’ original study, women compared the degree of saturation of their pads and tampons with those depicted on a chart. Lightly stained pads or tampons obtained a score of 1, moderately stained pads or tampons a score of 5, and soaked pads or tampons a score of 20. The scores were summed and a total score of greater than 100 per cycle was associated with a menstrual blood loss of greater than 80 mL. A drawback of the use of the chart is that it must be completed prospectively and its results are not available at the time of an initial evaluation. Additionally, the validity of the chart remains uncertain [11,12]. Nonetheless, in the last 5 years, the PBAC has been used successfully to monitor response to treatment in studies of women with bleeding disorders [13,14]. In most situations, however, the practitioner must rely on a menstrual history and clinical impression to decide whether a woman has menorrhagia. Warner et al. attempted to assess the volume of blood loss by means of specific clinical features.

In the last 20 years, our understanding of the needs of women with bleeding disorders has increased and our ability to manage their needs has improved. It is now well-established that heavy menstrual bleeding, or menorrhagia, is the most common symptom that women with bleeding disorders experience. Over the last 20 years, data have been published about the prevalence of menorrhagia in women with bleeding disorders. These data are summarized in Table 1. It has been well-established that menorrhagia is more prevalent among women with bleeding disorders. In the last 13 years, it has

also been established that bleeding disorders are more prevalent among women with menorrhagia. Among women with menorrhagia, the prevalence of von Willebrand disease (VWD) has been reported to be 5–20% [1–7] with an overall estimate of 13% [8] based on a systematic review. The prevalence of VWD and other bleeding selleck disorders in women with menorrhagia is summarized in Table 2. There are limited data regarding the prevalence of bleeding disorders among adolescents with menorrhagia, but in the last 8 years, it has become apparent that they are at least as likely to have an underlying

bleeding disorder as adult women with heavy menstrual bleeding. The prevalence of bleeding disorders in adolescents with menorrhagia (from studies of inpatients, outpatients and patients referred to a haemophilia of treatment centre) are summarized in Table 3. Menorrhagia is defined as heavy menstrual bleeding that lasts for more than 7 days [9] or results in the loss of more than 80 mL of blood per Ixazomib mouse menstrual cycle [9]. As measuring actual menstrual blood

loss is not feasible in clinical practice, Higham et al. devised a pictorial blood assessment chart (PBAC) as an alternative [10]. In the investigators’ original study, women compared the degree of saturation of their pads and tampons with those depicted on a chart. Lightly stained pads or tampons obtained a score of 1, moderately stained pads or tampons a score of 5, and soaked pads or tampons a score of 20. The scores were summed and a total score of greater than 100 per cycle was associated with a menstrual blood loss of greater than 80 mL. A drawback of the use of the chart is that it must be completed prospectively and its results are not available at the time of an initial evaluation. Additionally, the validity of the chart remains uncertain [11,12]. Nonetheless, in the last 5 years, the PBAC has been used successfully to monitor response to treatment in studies of women with bleeding disorders [13,14]. In most situations, however, the practitioner must rely on a menstrual history and clinical impression to decide whether a woman has menorrhagia. Warner et al. attempted to assess the volume of blood loss by means of specific clinical features.

We demonstrate here that HSCs are the major source of ADAMTS1, whose expression is increased nearly 250-fold upon full activation. MMP2 has been similarly associated with HSC activation during chronic liver injury, and, accordingly, we establish a clear correlation of ADAMTS1 and MMP2 expression in fibrotic liver samples. Taken together, our data identify ADAMTS1 as a new hub of the protease network that also contains the well-known MMP2 and is associated with liver fibrosis. The major regulatory step for all metalloprotease

activity in vivo occurs at the protein level and requires a primary proteolysis of the N-terminal prodomain. ADAMTS1 has been shown to undergo a second cleavage at the C-terminal end, leading to a shorter form that lacks the selleck compound two carboxy-terminal TSP1 repeats and has a reduced ability to bind to the ECM.32 Here, Dasatinib we describe, for the first time, the role of HSCs in the synthesis of a full-length 110-kDa unprocessed polypeptide secreted as the p87 active form. We also detected the shorter 65-kDa form that has been suggested

to reflect an inactivation pathway for p87. In addition, we show that only the 87-kDa active form is detected during chronic liver injury, suggesting that the p65-kDa form does not accumulate within liver tissue. Similar observations have been reported in non-small-cell lung carcinomas.33 However, characterization of ADAMTS1 forms within human tissues remains poorly documented, and their contribution to the onset and development of disease is still unclear. A mechanistic understanding of the effect of ADAMTS1 during liver fibrosis may be deduced from its catalytic activity against matrix components, such Mannose-binding protein-associated serine protease as aggrecan, versican, and nidogen. However, metallopeptidase

activities are highly redundant, and genetic inactivation of many metallopeptidases leads to minimal phenotypes. Moreover, no alteration of aggrecan turnover was found in ADAMTS1 knockout mice.34 In contrast, loss-of-function ADAMTS1 studies have shown severe embryonic and perinatal lethality, suggesting an implication in development35, 36 that may be related to its noncatalytic functions that depend on interactions with growth factors, such as vascular endothelial growth factor and fibroblast growth factor-2.37, 38 We now demonstrate that ADAMTS1 also interacts with the profibrotic cytokine, TGF-β, leading to its release from its latent to active forms. Increased ADAMTS1 expression during chronic liver injury contributes to TGF-β-dependent transcriptional activity and, hence, to liver fibrosis. This interpretation is in line with the recent report of the implication of ADAMTS1 in the stimulation of the stromal reaction in lung cancer, including induction of TGF-β and collagen.

To confirm this hypothesis, the apoptotic index was compared between TAT-transfected and vector-transfected HCC cells by TUNEL staining. After STS treatment, TUNEL analysis revealed that the apoptotic index in Vec-7703 cells (13.6% ± 0.7%) was significantly lower than that of TAT-c2 (61.7% ± 3.9%, P < 0.05) or TAT-c3 (40% ±

1.4%, P < 0.05), confirming that TAT had a proapoptotic ability (Fig. 5B). Similarly, the apoptotic index in Vec-7402 cells (19.6% ± 1.7%) was also significantly lower this website than that of TAT-7402 (70.1% ± 3.5%, P < 0.05) after STS treatment (Fig. 5C). In addition, immunofluorescence staining showed that TAT was colocalized with mitochondria in TAT-transfected cells (Supporting Fig. 1). To elucidate the molecular basis of apoptosis induced by TAT, we studied its role in the potentially proapoptotic mitochondrial permeability transition (MPT) event, which was measured by loss of mitochondrial ΔΨm using JC-1 dye. Red/orange fluorescence indicates intact mitochondria, Selleckchem LY294002 whereas green fluorescence indicates a collapse in mitochondrial ΔΨm. The result showed that the mitochondrial permeability and apoptotic index were similar before STS treatment (Fig. 5D). However, the mitochondrial permeability and apoptotic

index were significantly increased in TAT-7703 cells than that in Vec-7703 cells (67.5% ± 4.5% versus 17.8% ± 4.1%, P < 0.05) after STS treatment (Fig. 5D). Western blot analysis also showed that the release of Cyt-c into cytoplasm and cleavages of caspase-9 and PARP was dramatically increased in TAT-7703 cells after STS treatment compared with Vec-7703 (Fig. 5E). No obvious difference of caspase-8 was detected between the TAT-7703 and Vec-7703 cells. In addition, the mutant TAT could not induce apoptosis after STS treatment (Supporting Fig. 2E,F). To study the importance of TAT in regulating cell apoptosis, RNAi was used to knockdown endogenous TAT expression in PLC8024 cells. The result Thalidomide showed that siRNA against TAT could significantly reduce TAT expression in

PLC8024 cells (Fig. 6A) and MPT assay showed that strong red fluorescence was observed after STS treatment, indicating that these cells obtained an antiapoptotic ability (Fig. 6B). This result was further confirmed by immunoblotting analysis, showing that knockdown of TAT could inhibit the cleavages of caspase-9 and PARP (Fig. 6C). Deletion of 16q is one of the most frequent genetic alterations in HCC, implying the existence of a tumor suppressor gene on 16q.2, 3, 12, 13 Loss of 16q was also frequently detected in other solid tumors including breast,14 lung,15 and gastric cancers,16 suggesting that 16q may harbor one or more TSGs and its inactivation plays a key role in the pathogenesis of many malignancies including HCC. In this study we characterized one candidate TSG, TAT, at 16q22.1. The accurate frequency of loss of TAT allele in 50 HCC cases was characterized by qPCR.

147 Higher LCFA oxidation was found in liver mitochondria and peroxisomes isolated from ob/ob mice (Table 1).57,149,152,153 Increased mtFAO capacity in ob/ob liver was associated with enhanced CPT activity and/or CPT1 expression,109,152,154 and higher expression Dinaciclib mw of other mtFAO enzymes.119,154-157 Moreover,

PPARα expression is augmented in ob/ob liver,109,154,158 although some studies found normal or reduced PPARα expression.157,159 In db/db mice, mtFAO was enhanced in one study,160 whereas total hepatic FAO was decreased in another report (Table 1).161 PPARα expression in db/db liver was either increased,109,162,163 unchanged,164-166 or decreased.167,168 In ob/ob mice, hepatic mitochondrial oxidation of glutamate (providing electrons to complex I) was either unchanged or increased, whereas that of succinate (providing electrons to complex II) was consistently enhanced (Table 1).152,169-171 In db/db liver, glutamate and succinate-driven mitochondrial respiration was increased.170 However, the activity of different hepatic MRC complexes was significantly reduced in ob/ob57,58,172,173 and db/db mice (Table 1).172,174,175 These data, reporting higher (or normal) rates of oxygen consumption and reduced activity of different MRC complexes, are not necessarily selleck screening library discordant. Indeed, mitochondrial respiration is significantly impaired only when

the activity of MRC complexes is severely inhibited.176 An important ATP depletion was observed in ob/ob liver,171,177 which could be due to OXPHOS uncoupling.171,178 Finally, electron microscopic analysis of ob/ob liver showed enlarged mitochondria with abnormal cristae organization

and granular matrix, but without crystalline inclusions.153 Taken together, these data in ob/ob and db/db indicated higher of oxidative capacity of liver mitochondria with different respiratory substrates including FAs, but impaired activity of different MRC complexes. These mitochondrial alterations are leading to ROS overproduction since more substrate-derived electrons are entering the MRC and leak from complexes I and III.5,7,17,63,171 Increased hepatic mtFAO in ob/ob and db/db mice was associated with higher, normal, or even reduced PPARα expression. The exact reasons of this discrepancy are not known, but differences in age and diet could be involved. Three studies assessed whole-body 13C-octanoate oxidation in patients with NASH. In one study, patients with NASH had higher whole-body 13C-octanoate oxidation when compared to the controls,72 whereas the other studies showed no difference (Table 1).179,180 Using indirect calorimetry and KB production as surrogate markers of mtFAO, other investigations found higher fat oxidation in patients with NASH.42,71,97,181 In contrast, reduced PPARα mRNA expression was found in patients with NASH compared to patients with simple fatty liver,111,113,182 thus suggesting that PPARα induction progressively declines when fatty liver progresses to NASH.