CDT1 is a Potential Therapeutic Target for the Progression of NAFLD to HCC and the Exacerbation of Cancer.

We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as mean ± standard deviation. Significant statistical level was chosen as p = 0.05.Our results demonstrate in a cohort from Turkey that rs738409 C > G polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.

e16199 Background: Primary liver cancer is the third most frequent cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) composing 75% of cases. Recent preclinical models suggest that immunotherapy targeting programmed cell death protein 1 (PD-1) leads to CD8+ T-cell activation but not tumor regression in nonalcoholic fatty liver disease (NAFLD) induced HCC. However, additional studies are required to understand the response of NAFLD-associated HCC patients to PD-1 and programmed death-ligand 1 (PD-L1) therapies. Methods: Our team conducted a retrospective, single center study to determine the best responses to anti-PD-1/PD-L1 containing regimens in patients with HCC and underlying NAFLD cirrhosis. There were 2 groups included in this study: patients with HCC associated with NAFLD cirrhosis and those who had HCC without NAFLD cirrhosis. All patients included in this study received either an anti-PD-1/PD-L1 targeted agent as monotherapy or combined with other systemic treatment. Radiologic evaluations were conducted between February 2018 and January 2022. Results: There were 81 patients were included in this study: 15 in the NAFLD cirrhosis HCC group and 66 in the HCC group without NAFLD cirrhosis. When determining the best responses to anti-PD-1/PD-L1 therapies, 6 patients (40%) with HCC and NAFLD cirrhosis had disease progression as their best responses versus 7 patients (10.6%) who had HCC without NAFLD cirrhosis (risk ratio 3.8, p = 0.012). Furthermore, in the HCC group without NAFLD cirrhosis, 59 patients (89.4%) experienced disease control (defined as stable disease, partial response, or complete response) from anti-PD-1/PD-L1 containing regimens compared to 9 patients (60%) in the NAFLD cirrhosis-related HCC group (risk ratio 1.5, p = 0.012). No significant differences were found in gender, patient age, or treatment regimens received between the two groups. See the table below for details on immunotherapy regimens and treatment responses. Conclusions: In this study, HCC patients with NAFLD cirrhosis experienced significantly higher rates of disease progression as the best response to anti-PD-1/PD-L1 therapies compared to HCC patients without NAFLD cirrhosis. As the use of immunotherapy in the HCC population continues to expand, additional prospective studies are necessary to clarify the impact of underlying liver disease on treatment response.[Table: see text]

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Nonalcoholic Fatty Liver Disease and Fibrosis Progression: The Good, the Bad, and the Unknown

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continuously increasing, with the proportion of patients with liver carcinogenesis due to non-alcoholic steatohepatitis (NASH) rising accordingly. Although it is important to identify individuals with hepatic carcinogenesis among patients with NAFLD, useful biomarkers have not yet been established. Previously, in a mouse model of diabetes mellitus without genetic modifications, we reported that a high-fat diet increases serine palmitoyltransferase long chain subunit 3 (SPTLC3) expression in liver tissue, accompanied by high frequency of liver carcinogenesis. Serine palmitoyltransferase (SPT) catalyzes the metabolism of fatty acids, particularly sphingolipid synthesis, and SPTLC3 has been identified as its catalytic subunit, but its role in liver disease is unclear. In the present study, the importance of SPTLC3 in NAFLD development was investigated. SPTLC3 mRNA expression was observed in a liver cancer cell line and in liver tissues from patients with NAFLD and liver cancer. In total, 99 patients with NAFLD (66 without hepatocellular carcinoma (HCC) and 33 with HCC were recruited, having been diagnosed by liver biopsy or imaging, along with 6 healthy volunteers (HVs). Serum was collected from patients and HVs, and SPTLC3 level was assessed by ELISA. SPTLC3 expression was higher in non-cancerous compared with that in cancerous liver tissues. Serum SPTLC3 levels were negatively correlated with platelet count and positively correlated with hyaluronic acid levels, suggesting an association with liver fibrosis. Moreover, SPTLC3 levels were significantly higher in the HCC group than in the HV and NAFLD groups. Multivariate analysis of HCC-related factors identified platelets, alanine transferase, albumin and SPTLC3 as independent factors associated with HCC. Furthermore, in patients with other chronic liver diseases (hepatitis B and C, and alcoholic liver disease), no significant differences in serum SPTLC3 levels were observed between patients with or without HCC. Thus, SPTLC3 expression increases specifically with the progression of NAFLD. Overall, the present results indicate that SPTLC3 may be involved in the development of liver carcinogenesis during NAFLD.

Aim: to determine the frequency of PNPLA3 rs738409 C>G gene polymorphism, leading to p.I148M substitution, in patients with non-alcoholic fatty liver disease (NAFLD), and to reveal the association between polymorphism and probable NAFLD outcomes: liver cirrhosis (LC) and hepatocellular carcinoma (HCC).Materials and methods. The study was conducted according to the “case-control” design, three main groups were formed: a group with NAFLD (n = 46), a group with LC (n = 61), a group with HCC (n = 50), as well as a control group (n = 70), for all groups we performed genotyping of the rs738409 polymorphism of the PNPLA3 gene. The relationship between the occurrence of different genotype variants and the diagnosis of patients was evaluated, the odds ratio (OR) of progression of NAFLD and the reliability of intergroup differences were determined.Results. NAFLD patients with PNPLA3 I148M polymorphism have a significantly higher chance of developing LC and HCC. The odds ratio for the GG genotype was 7.94 (95 % Cl: 2.19–28.84; p = 0.030) for LC and 6.51 (95 % Cl: 1.15–4.08; p = 0.039) — for HCC with concomitant LC. The presence of the minor G allele also increases the likelhood of transition from NAFLD to LC (OR = 2.38; 95 % Cl: 1.41–4.02; p = 0.010) and HCC in the presence of cirrhosis (OR = 2.17; 95 % Cl: 1.15–4.08; p = 0.039). Differences in the frequency of PNPLA3 polymorphism between the NAFLD and HCC groups were not significant. Additional risk factors for HCC associated with NAFLD are overweight (OR = 5.14; 95 % Cl: 1.94–13.67; p < 0.001), arterial hypertension (OR = 8.49; 95 % Cl: 3.05–23,62; p < 0.001) and diabetes mellitus (OR = 8.57; 95 % Cl: 1.03–71.48; p = 0.032).Conclusion. The frequency of single nucleotide polymorphism PNPLA3 significantly differs in patients with NAFLD, cirrhosis and HCC compared with the control group of healthy volunteers. The PNPLA3 I148M polymorphism increases the incidence of NAFLD progression to cirrhosis and HCC, but only with concomitant cirrhosis.

This study aimed to compare the long-term cumulative recurrence rates of hepatocellular carcinoma (HCC) and prognosis after curative resection for HCC in noncirrhotic patients with nonalcoholic fatty liver disease (NAFLD) versus hepatitis B virus (HBV) infection. We retrospectively analyzed the data of 791 patients without recurrence within 1 year after curative resection for HCC from January 2005 to December 2015. Of these, 63 and 728 were NAFLD and HBV patients without cirrhosis, respectively. Recurrence of HCC was observed in 6 (9.5%) and 210 (28.8%) patients in the NAFLD and HBV groups, respectively, during median follow-ups of 69.9 and 85.2 months. Cumulative recurrence rates in the NAFLD group at 2, 4, 6, 8 and 10 years (3.6, 9.4, 12.4, 12.4 and 12.4%, respectively) were significantly lower than in the HBV group (1.7, 16.9, 27.2, 37.1 and 44.4%, respectively) ( P = 0.008). Cumulative overall survival (OS) rates in the NAFLD group at 2, 4, 6, 8 and 10 years (98.2, 96.0, 84.0, 84.0 and 84.0 %, respectively) were significantly lower than in the HBV group (99.3, 98.4, 97.3, 95.7 and 93.6%, respectively) ( P = 0.003). HBV infection, with or without fatty liver compared to NAFLD, were significant predictors for the recurrence of HCC ( P < 0.05 for all) and OS ( P < 0.05 for all), respectively. Noncirrhotic NAFLD patients showed lower recurrence rates of HCC but poorer survival outcomes than noncirrhotic HBV patients with or without fatty liver. The recurrence risk of HCC remains even in noncirrhotic NAFLD patients.

Background: Non alcoholic fatty liver disease (NAFLD) is an independent risk factor of cardiovascular disease (CVD). In this research, we want exploring the relationship between NAFLD, visceral fat thickness and the severity of coronary artery disease. Methods: 1, The relationship between NAFLD, visceral fat thickness and severity of coronary heart disease(323 people). 2, The correlation between severe NAFLD and visceral fat thickness in the severe stenosis of coronary heart disease(197 people). Results: 1, the proportion of NAFLD was significantly increased by 16% and 19% in different coronary artery stenosis than in the normal group. Along with the increasing degree of coronary artery stenosis, the total visceral fat thickness increase, especially the epicardial layer (the moderate stenosis increased by 23% and the severe stenosis increased by 54% than without stenosis). 2, In the severe coronary artery stenosis group, the patients were divided into NAFLD group and non NAFLD group. compared to non NAFLD group, the epicardial, liver, renal, before the perirenal fat and the coronary score significantly increased in the NAFLD group (10%, 22%, 32%, 36% and 27%, respectively) .Along with the increase of coronary score , the epicardial fat thickness was increased significantly (16% and 34%, respectively) in the non NAFLD group; but the epicardial thickness of the NAFLD group was slightly increased (8% and 8%, respectively), there was no significant difference among the subgroups. Furthermore,not only in NAFLD group but also in non NAFLD group, the visceral fat thickness of the other three sections have no significant change among the three subgroups. Conclusion: Both the NAFLD and the epicardial adipose layer thickening can increase the risk of coronary artery stenosis. In the patients with the severe coronary artery stenosis, the NAFLD patients are more likely to increase the accumulation of the visceral fat thickness than the non NAFLD patients. Under the same thickness of the epicardium, the degree of coronary artery lesions is lighter in the NAFLD patients; it may be related to AMPK wich may have the myocardial protective effects.

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The most common underlying causes of Hepatocellular car-cinoma (HCC) are chronic liver diseases and cirrhosis. Aim of Study: Our study aimed to investigate the serum estradiol levels in patients with nonalcoholics steatohepatitis (NASH) related HCC and to explore their correlations with clinicopathological features of HCC. Patients and Methods: A Controlled Cross-Sectional Study included 200 patients with NAFLD (181 patients with NAFLD and 23 patients with NAFLD related HCC) and 50 controls. Serum estradiol was measured by enzyme-linked immuno-sorbent assay (ELISA). Results: The serum level of estradiol was significantly lowered in patients with NAFLD (32.24±7.3pg/ml) compared to controls (42.9±3.9pg/ml). Moreover, our findings revealed lower concentrations of serum estradiol in the HCC group (28.6±5.3pg/ml) compared to the NAFLD group (33.45 ±4.3pg/ml, p<0.00 1). We found significant negative correla-tions between serum estradiol levels and clinicopathological features of HCC (portal vein thrombosis, lymph node metas-tasis, number of tumor lesions, advanced clinical stage, tumor size, tumor site, distant metastasis) in patients with NAFLD complicated with HCC. linear regression test and we observed that serum triglycerides and a-fetoprotein were significantly associated with serum estradiol among the HCC group. Conclusion: Serum estradiol level was significantly low-ered in the HCC subgroup compared to the NAFLD group and negatively correlated with clinicopathological features of HCC. Serum estradiol can be used as a promising predictor of HCC in female patients with NAFLD.

BACKGROUNDPrevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing, and NAFLD has become one of the most common chronic liver diseases worldwide. With abnormal CD44 activation, the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Thus, the molecular mechanism of CD44 in NAFLD needs to be identified.AIMTo investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.METHODSSprague-Dawley rats were fed a high-fat (HF) for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide (0.05%) to induce HCC. Rats were sacrificed every 2 wk, and subsequently divided into the groups based on liver pathological examination (hematoxylin and eosin staining): NAFLD, denaturation, precancerosis, HCC, and control. Liver CD44 mRNA was detected by OneArray. Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density. Serum CD44, alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, and AFP levels were quantitatively tested.RESULTSElevated CD44 was first reported in hepatocarcinogenesis, with increasing expression from NAFLD to HCC at the protein or mRNA level. The CD44 integral optic density values were significantly different between the control group and the NAFLD (t = 25.433, P < 0.001), denaturation (t = 48.822, P < 0.001), precancerosis (t = 27.751, P < 0.001), and HCC (t = 16.239, P < 0.001) groups, respectively. Hepatic CD44 can be secreted into the blood, and serum CD44 levels in HCC or precancerous rats were significantly higher (P < 0.001) than those in any of the other rats. Positive correlations were found between liver CD44 and CD44 mRNA (rs = 0.373, P = 0.043) and serum CD44 (rs = 0.541, P = 0.002) and between liver CD44 mRNA and serum CD44 (rs = 0.507, P = 0.004). Moreover, significant correlations were found between liver CD44 and liver AFP (rs = 0.572, P = 0.001), between serum CD44 and serum AFP (rs = 0.608, P < 0.001), and between CD44 mRNA and AFP mRNA (rs = 0.370, P = 0.044).CONCLUSIONThe data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.

The increasing burden of non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD encompasses a spectrum of liver disease, ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With the pandemic of obesity and type 2 diabetes mellitus (T2DM), there has been an exponential growth in the prevalence of NAFLD over the past two decades. The prevalence of NAFLD in most Asian countries, including China, is above 25% in the general adult population.[1] Furthermore, there is a developing childhood obesity pandemic, and a meta-analysis of 20,595 children in Asia generated a pooled NAFLD prevalence of 5.53%, which had increased by approximately 1.6-fold since 2010. The pooled prevalence of NAFLD in Asian children increased from those with normal weight (1.5%) to those who were overweight (16.7%) or obese (50.1%).[2] A recent study suggested that NAFLD is not uncommon in lean Chinese adults with a normal waist circumstance. Metabolic risk factors, rather than genetic factors, may play an important role in the development of lean NAFLD,[3] and the hepatic and extra-hepatic complications can also develop in lean patients, which reinforces the importance of considering metabolic phenotype in the assessment of NAFLD, rather than using body mass index-based approaches.[4] Renaming of NAFLD to MAFLD: A diagnosis of NAFLD is made on the basis of histological or imaging-derived evidence of steatosis, in the absence of a known etiology of fatty liver. With advances in knowledge of the pathogenesis of the condition, the "exclusive" term NAFLD no longer serves to precisely describe a highly heterogeneous disease. In 2020, the novel term of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in an attempt to create an "inclusive" diagnosis.[5] Zeng et al[6] performed a cross-sectional study of Chinese adults which showed that the prevalence of MAFLD is higher than that of NAFLD, and therefore the newly-defined label of MAFLD may better reflect the metabolic pathogenesis. Furthermore, a pathologic analysis of patients with MAFLD showed that a single metabolic defect can have a significant role in the development of fibrosis and that insulin resistance plays a key role in the progression of steatohepatitis and the development of significant fibrosis.[7] As Zheng et al discussed, by using the new terminology, "cryptogenic cirrhosis" and MAFLD can now be diagnosed in lean individuals using metabolic criteria, rather than being viewed as completely separate entities. The renaming of NAFLD to MAFLD may result in significant improvements in awareness, advocacy, research, and the clinical management of the condition.[8] Update on the pathogenesis of MAFLD: The pathogenesis of NAFLD/MAFLD is a multifactorial process, involving interactions among nutrition, metabolism, genetic predisposition, the gut microbiota, and environmental factors. Although a great deal of progress has been made in recent decades, the pathogenic mechanism of NAFLD/MAFLD has yet to be fully elucidated. In this issue of the Chinese Medical Journal (CMJ), Pan et al[9] give an overview of the role of hepatocyte nuclear factor 4α (HNF4α) in the pathogenesis of NAFLD. HNF4α has been shown to regulate bile acid, lipid, and glucose metabolism; and hepatic HNF4α expression is much lower in patients with NAFLD and mouse models of NASH. Furthermore, there is evidence that hepatic HNF4α plays a key role in the initiation and progression of NAFLD and may represent a therapeutic target for NAFLD.[9] Huang et al[10] presented a systematic review regarding the role of retinol-binding protein 4 (RBP4) in the development of NAFLD and its potential therapeutic application. RBP4 induces hepatic de novo lipogenesis, impairs fatty acid oxidation, increases insulin resistance, and promotes hepatic inflammation. Furthermore, a high plasma RBP4 concentration is associated with a high risk of NAFLD; and agents that reduce the circulating RBP4 concentration and/or hepatic RBP4 expression have a protective effect against NAFLD. These findings suggest that RBP4 could be targeted as a novel diagnostic marker or therapeutic target for NAFLD.[10] Jackson et al[11] summarized the essential physiology of bile acid and sphingolipid metabolism, because the dysregulation of both are potential contributors to NAFLD. Specifically, the dysregulation of bile acid and sphingolipid metabolism has been linked to hepatic steatosis, inflammation, and fibrosis, and the further exploration of the pathologic effects mediated by bile acids and sphingolipids may also lead to new diagnostic and therapeutic strategies for NAFLD. Hepatitis B and concurrent MAFLD: Concomitant NAFLD/MAFLD in patients with chronic hepatitis B (CHB) has become highly prevalent over the past two decades. However, the risks associated with the dual etiologies, outcomes, and mechanisms involved in the interaction between CHB and NAFLD have not been fully characterized. Tong et al[12] summarize the findings of recent clinical and basic research studies related to the potential interactions between CHB and NAFLD. The prevalence of hepatic steatosis in CHB has been reported to be 32.8% (95% CI, 28.9%–37.0%); and it is higher in men and patients with obesity. The presence of hepatic steatosis in patients with CHB is related to metabolic, rather than viral factors. Patients with both CHB and NAFLD are more likely to experience liver-related outcomes or death than those with CHB alone. Many studies have shown that steatosis is positively associated with the clearance of hepatitis B virus (HBV) surface antigen and a reduction in HBV DNA, and the prevalence and incidence of NAFLD in patients with CHB may be lower than in those without. In Chang and colleagues' multi-center, prospective study of 1000 treatment-naïve patients with biopsy-confirmed CHB, NASH was found in 182 patients (18.2%), 46% of these achieved resolution of NASH, and only 4% of the patients developed new-onset NASH after 72 weeks of entecavir treatment. Body mass at baseline and a slight weight change during follow-up were associated with the prevalence, incidence, and remission of NASH in patients with CHB.[13] Finally, steatosis is more prevalent in patients with CHB and is a common reason for abnormal circulating liver enzyme activities in infected patients with a low HBV-DNA load or a good response to infection. From MAFLD to HCC: Although viral hepatitis remains the most common etiology of liver cancer-related deaths, NAFLD is the most rapidly growing contributor to mortality and morbidity related to liver disease in the world. The global burden of HCC is increasing alongside the NAFLD pandemic. A recently published review in CMJ summarizes the characteristics of NAFLD-related HCC.[14] The incidence of NAFLD-related HCC is much higher in patients with severe steatohepatitis, advanced fibrosis, and cirrhosis than in individuals with NAFLD in general, and it is most likely to occur in older men with metabolic syndrome. The incidence of HCC in patients with NAFLD-related cirrhosis is lower than that in those with hepatitis C virus- or HBV-related cirrhosis. Compared with HCCs of other etiologies, NAFLD-related HCCs are generally large, well-differentiated, solitary lesions with a higher level of inflammatory infiltration, and they are less likely to metastasize extra-hepatically. Moreover, NAFLD-related HCC is more likely to develop in the absence of cirrhosis.[14] In a recent issue of CMJ, Rios et al reviewed the progression of MAFLD to HCC and stated that lipotoxicity, insulin resistance, oxidative stress, chronic inflammation, multiple gene mutations, and alterations to the fecal microbial composition are the most important factors determining hepatic carcinogenesis, whereas steatohepatitis and fibrosis are not essential for the development of HCC in obesity-related fatty liver disease.[15] Non-invasive diagnosis of MAFLD: Accumulating evidence suggests that non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict its prognosis. In a recent issue of CMJ, Li et al review new developments in non-invasive testing for NAFLD, with respect to steatosis, steatohepatitis, and fibrosis.[16] For the identification of steatosis, ultrasonography remains the most common method, because of its wide availability and low cost, but magnetic resonance imaging-proton density fat fraction is currently the most accurate means of identifying hepatic steatosis, and transient elastography (TE) represents a promising technique for the evaluation of hepatic steatosis and fibrosis. Except for the widely used controlled attenuation parameter, ultrasonographic attenuation has been reported to have a low failure rate and shows moderate-to-high performance for the discrimination of degrees of steatosis in patients with chronic liver disease.[17] Various non-invasive algorithms, such as the fatty liver index (FLI) and hepatic steatosis index (HSI), have been used as screening tests for steatosis in epidemiologic studies. In Chen et al's study, both FLI and HSI were shown to be useful screening tools for NAFLD in adults with obstructive sleep apnea/hypopnea syndrome.[18] In patients with steatohepatitis, some circulating biomarkers correlate with the severity of NASH but show modest predictive accuracy. Regarding liver fibrosis, liver stiffness measurement (LSM) using TE is highly accurate and is widely used worldwide. Magnetic resonance elastography is marginally better than TE, but it is limited by its cost and availability. In contrast, simple fibrosis scores, such as the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score, can be easily calculated and are recommended for use in primary care. These scores and LSM have sufficiently high negative predictive values to exclude advanced fibrosis. Recently, Shi et al found that the combination of the presence of a metabolic disorder and the FIB-4 index provides for a more accurate diagnosis of advanced fibrosis in patients with NAFLD.[19] Thus, as part of the redefinition of MAFLD, metabolic risk factors should be taken into account during diagnosis and management. Therapeutic approaches to MAFLD: In a recent issue of CMJ, Shi et al[20] discuss recent advances and provide a perspective regarding the treatment of MAFLD. Weight management through an appropriate diet and physical activity remains the most important component of the treatment of MAFLD. Weight loss through bariatric surgery may be an effective means of achieving significant improvements in patients with morbid obesity and MAFLD. Although numerous agents, including novel modulators of glucolipid metabolism, are being assessed in clinical trials, there is still no approved drug for the treatment of MAFLD. The nomenclature of MAFLD emphasizes the existence of concomitant metabolic disorders and obesity, and patients with MAFLD are therefore subject to both hepatic and other metabolic risks. Thus, drugs targeting underlying cardiometabolic risk factors are essential to improve the outcomes of patients with MAFLD. The screening of patients who are at a high risk of MAFLD and the provision of a comprehensive individual therapeutic program are critical. For example, patients with MAFLD and T2DM would benefit from the use of antidiabetic agents, patients with overweight or obesity would gain greater benefit from weight management, and those with metabolic syndrome require comprehensive individualized management. These therapeutic approaches might help identify the patients with MAFLD who are at the greatest risk of disease progression and facilitate more precise and appropriate management. Summary and prospects: The growing burden of NAFLD parallels the increasing prevalences of obesity and metabolic syndrome worldwide. Cardiometabolic risk factors have a bidirectional relationship with NAFLD. The majority of patients with NAFLD meet the diagnostic criteria for MAFLD, and this represents a more appropriate term. Further clinical studies of the changes created by the redefinition of NAFLD/MAFLD, including the epidemiologic character, prognosis, diagnosis, prevention, and treatment of the condition, are required. Currently, MAFLD and CHB are increasingly being diagnosed in the same individuals, and the pathophysiological interaction between MAFLD and HBV infection in patients is worthy of further exploration. The long-term outcomes of MAFLD are related to the severity of metabolic dysfunction and liver fibrosis, rather than obesity. Metabolic syndrome and T2DM are the most important risk factors for MAFLD-related cirrhosis and HCC. A lack of awareness regarding the factors underlying MAFLD-related HCC may lead to delay in its diagnosis. The further development and validation of non-invasive diagnostic techniques and clinical pathways will help clinicians assess the severity of MAFLD, categorize patients, and identify those requiring specific treatments. There is still no effective approved drug for MAFLD, but the in-depth study of pathologic mechanisms may provide new therapeutic targets. Measures to increase awareness and treat or prevent the associated cardiometabolic diseases are necessary to reduce the growing burden of MAFLD. Funding This study was supported by grants from the National Key Research and Development Program of China (No. 2021YFC2700802), the National Natural Science Foundation of China (Nos. 81900507 and 82170593). Conflicts of interest None.

T1015 Risk Factors for Hepatocellular Carcinoma in Patients with Nonalcoholic Steatohepatitis

Background: Nonalcoholic fatty liver disease (NAFLD) is the fastest-rising cause of end-stage liver disease for liver transplantation. The underlying mechanisms of NAFLD disease progression from nonalcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) remain unclear. It has been well-accepted that inflammation and dysregulation of sphingolipid metabolism are two important contributors to NASH progression. Recent advances in gene profiling technologies have significantly improved the current understanding of NASH-HCC pathogenesis. However, the key pathway changes underlying liver fibrosis and dysregulation of sphingolipid metabolism haven’t been fully elucidated and are the focus of this study. Methods: DIMOND NASH mouse model (C57BL/6J and 129S1/SvlmJ mixed background) was used in this study. Male mice (21 to 24-week-old) were fed with WDSW (Western diet, Harlan, TD88137, and a high fructose-glucose solution, 23.1g/L D-fructose plus 18.9g/L D-glucose) or standard chow diet ad libitum for six months or one year. At the end of the study, liver tissues were harvested for total RNA isolation using Trizol. Gene profiles were analyzed using the NanoString nCounter® Gene Expression Fibrosis V2 panel with sphingolipid metabolism pathways. The differentially expressed genes (DEGs) between groups were determined using Rosalind. QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the DEGs. Human HCC patient data were downloaded from The Cancer Genome Atlas Program (TCGA). The sphingolipid profiles in the serum and liver were determined using LC-MS/MS. Results: All the mice developed NASH and HCC after feeding with WDSW for 6 months and 1 year, respectively. Bioinformatic analysis identified 191 DEGs in the NASH group and 250 DEGs in HCC group compared to the corresponding controls. The IPA analysis revealed that the major pathways related to inflammation and fibrosis were upregulated in both NASH and HCC mice. The expression levels of key genes related to ceramide synthesis and metabolism [serine palmitoyltransferase long chain base subunit 2 (Sptlc2), ceramide synthase 6 (Cers6), N-acylsphingosine amidohydrolase 2 (Asah2)] and sphingosine-1-phosphate receptor 2 (S1PR2) were significantly upregulated in NASH mice. In HCC group, Cers5, Cers6, sphingomyelin synthase 1 (Sgms1), Asah1, and S1PR3 were significantly increased. The expression levels of sphingosine kinase 2 and S1P lyase 1 were decreased both in NASH and HCC. Analysis of the TCGA data set showed that CERS5, CERS6, SPTLC2, ASAH1 and SGMS1 were highly expressed in HCC compared to healthy controls. The LC-MS/MS data also showed significant changes in sphingolipid profiles in serum and liver NASH and HCC. Conclusion: Our study suggests that dysregulated sphingolipid metabolism is associated with NASH and HCC disease progression. Further validation and research are needed for the potential application of sphingolipid profiles as diagnostic or prognostic markers in the clinic. This study was supported by VA Merit Award I01BX004033; Research Career Scientist Award (IK6BX004477); VA ShEEP grants (1IS1BX005517-01 and 1 IS1 BX004777-01) National Institutes of Health Grant R01 DK104893, R01DK-057543 and R21 AA026629-01. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The changing epidemiology of liver diseases in Asia.