BACKGROUND AND AIM: Remnant cholesterol (remnant-C) mediates the progression of major adverse cardiovascular events. It is unclear whether remnant-C, and particularly cumulative exposure to remnant-C, is associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether remnant-C, not only baseline but cumulative exposure, can be used to independently evaluate the risk of NAFLD. METHODS: This study included 1 cohort totaling 21,958 subjects without NAFLD at baseline who underwent at least 2 repeated health checkups and 1 sub-cohort totaling 2,649 subjects restricted to those individuals with at least 4 examinations and no history of NAFLD until Exam 3. Cumulative remnant-C was calculated as a timeweighted model for each examination multiplied by the time between the 2 examinations divided the whole duration. Cox regression models were performed to estimate the association between baseline and cumulative exposure to remnant-C and incident NAFLD. RESULTS: After multivariable adjustment, compared with the quintile 1 of baseline remnant-C, individuals with higher quintiles demonstrated significantly higher risks for NAFLD (hazard ratio [HR] 1.48, 95%CI 1.31-1.67 for quintile 2; HR 2.07, 95%CI 1.85-2.33 for quintile 3; HR 2.55, 95%CI 2.27-2.88 for quintile 4). Similarly, high cumulative remnant-C quintiles were significantly associated with higher risks for NAFLD (HR 3.43, 95%CI 1.95-6.05 for quintile 2; HR 4.25, 95%CI 2.44-7.40 for quintile 3; HR 6.29, 95%CI 3.59-10.99 for quintile 4), compared with the quintile 1. CONCLUSION Elevated levels of baseline and cumulative remnant-C were independently associated with incident NAFLD. Monitoring immediate levels and longitudinal trends of remnant-C may need to be emphasized in adults as part of NAFLD prevention strategy.
Adult ; Humans ; Cohort Studies ; Non-alcoholic Fatty Liver Disease/etiology* ; Cholesterol ; Proportional Hazards Models ; Risk Factors

Aged ; Humans ; Non-alcoholic Fatty Liver Disease/etiology* ; China/epidemiology*

BACKGROUND: China and the United States (US) ranked first and third in terms of new liver cancer cases and deaths globally in 2020. Therefore, a comprehensive assessment of trends in the incidence of primary liver cancer with four major etiological factors between China and the US during the past 30 years with age-period-cohort (APC) analyses is warranted. METHODS: Data were obtained from the Global Burden of Disease 2019, and period/cohort relative risks were estimated by APC modeling from 1990 to 2019. RESULTS: In 2019, there were 211,000 new liver cancer cases in China and 28,000 in the US, accounting for 39.4% and 5.2% of global liver cancer cases, respectively. For China, the age-standardized incidence rate (ASIR) consecutively decreased before 2005 but increased slightly since then, whereas the ASIR continuously increased in the US. Among the four etiological factors of liver cancer, the fastest reduction in incidence was observed in hepatitis B virus-related liver cancer among Chinese women, and the fastest increase was in nonalcoholic steatosis hepatitis (NASH)-related liver cancer among American men. The greatest reduction in the incidence of liver cancer was observed at the age of 53 years in Chinese men (-5.2%/year) and 33 years in Chinese women (-6.6%/year), while it peaked at 58 years old in both American men and women (4.5%/year vs . 2.8%/year). Furthermore, the period risks of alcohol- and NASH-related liver cancer among Chinese men have been elevated since 2013. Simultaneously, leveled- off period risks were observed in hepatitis C viral-related liver cancer in both American men and women. CONCLUSIONS Currently, both viral and lifestyle factors have been and will continue to play an important role in the time trends of liver cancer in both countries. More tailored and efficient preventive strategies should be designed to target both viral and lifestyle factors to prevent and control liver cancer.
Male ; Humans ; United States/epidemiology* ; Female ; Middle Aged ; Incidence ; Global Burden of Disease ; Non-alcoholic Fatty Liver Disease/complications* ; Cohort Studies ; Liver Neoplasms/etiology* ; China/epidemiology*

Globally, metabolic-asssociated fatty liver disease has become a significant health burden due to its complex pathogenesis, and there are no specific and effective therapeutic drugs to date. The onset and progression of metabolic-asssociated fatty liver disease is closely associated with improper dietary habits. The cornerstone to treat metabolic-asssociated fatty liver disease is weight loss through a well-balanced diet. This article summarizes and discusses the research progress at home and abroad in relationship to metabolic-asssociated fatty liver disease and dietary patterns such as the Mediterranean diet, the DASH diet, an energy-restricted balanced diet, a low fat diet, a low carbohydrate diet, a western diet, an animal food diet, a traditional diet, and others. In addition, it categorizes the effects of various dietary patterns on the prevention, treatment, or induction of several issues that need further metabolic-asssociated fatty liver disease research for subsequent reference.
Animals ; Non-alcoholic Fatty Liver Disease/etiology* ; Diet, Fat-Restricted ; Weight Loss ; Diet, Mediterranean ; Liver

The emergence of non-alcoholic fatty liver disease (NAFLD) as the leading chronic liver disease worldwide raises some concerns. In particular, NAFLD is closely tied to sedentary lifestyle habits and associated with other metabolic diseases, such as obesity and diabetes. At the end of the disease spectrum, non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), representing a serious health problem to modern society. Recently, an increasing number of HCC cases originating from this progressive disease spectrum have been identified, with different levels of severity and complications. Updating the current guidelines by placing a bigger focus on this emerging cause and highlighting some of its unique features is necessary. Since, the drivers of the disease are complex and multifactorial, in order to improve future outcomes, having a better understanding of NASH progression into HCC may be helpful. The risks that can promote disease progression and currently available management strategies employed to monitor and treat NASH-related HCC make up the bulk of this review.
Carcinoma, Hepatocellular/etiology* ; Humans ; Liver Cirrhosis ; Liver Neoplasms/etiology* ; Non-alcoholic Fatty Liver Disease ; Obesity

Objective: Liver fibrosis is an important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Peripheral artery disease (PAD) and liver fibrosis share many common metabolic dysfunctions. We aimed to explore the association between PAD and risk of fibrosis deterioration in NAFLD patients. Methods: The study recruited 1,610 NAFLD patients aged ≥ 40 years from a well-defined community at baseline in 2010 and followed up between August 2014 and May 2015. Fibrosis deterioration was defined as the NAFLD fibrosis score (NFS) status increased to a higher category at the follow-up visit. PAD was defined as an ankle-brachial index of < 0.90 or > 1.40. Results: During an average of 4.3 years' follow-up, 618 patients progressed to a higher NFS category. PAD was associated with 92% increased risk of fibrosis deterioration [multivariable-adjusted odds ratio ( ): 1.92, 95% confidence interval ( ): 1.24, 2.98]. When stratified by baseline NFS status, the for progression from low to intermediate or high NFS was 1.74 (95% : 1.02, 3.00), and progression from intermediate to high NFS was 2.24 (95% : 1.05, 4.80). There was a significant interaction between PAD and insulin resistance (IR) on fibrosis deterioration ( for interaction = 0.03). As compared with non-PAD and non-IR, the coexistence of PAD and IR was associated with a 3.85-fold (95% : 2.06, 7.18) increased risk of fibrosis deterioration. Conclusion PAD is associated with an increased risk of fibrosis deterioration in NAFLD patients, especially in those with IR. The coexistence of PAD and IR may impose an interactive effect on the risk of fibrosis deterioration.
Adult ; Aged ; Aged, 80 and over ; Ankle Brachial Index ; China ; epidemiology ; Female ; Humans ; Liver Cirrhosis ; epidemiology ; etiology ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease ; epidemiology ; etiology ; Peripheral Arterial Disease ; complications ; Prevalence ; Prospective Studies ; Risk Factors

BACKGROUND: Physical activity (PA) that includes an accumulated exercise regimen that meets or exceeds a certain intensity reduces intrahepatic fat, leading to the improvement of nonalcoholic fatty liver disease (NAFLD) in afflicted patients. However, whether an increase in comprehensive PA, including activities of daily living, contributes to ameliorating the pathophysiology of NAFLD remains unclear. This study aimed to examine whether PA improves liver function in patients with NAFLD. METHODS: The study included 45 patients with NAFLD who underwent follow-up examinations at least 6 months-but no later than 1 year-after their baseline examinations. The patients were interviewed about their daily activities and exercise habits to determine whether they had engaged in at least 3 metabolic equivalents (METs) per day during the previous 6 months; the quantity of PA, expressed in Ekusasaizu (Ex) units, was calculated as METs multiplied by hours. Patients who had achieved at least a 1-Ex increase in PA per week compared to baseline at the time of their follow-up interview (the PA increase group) were compared to those whose PA was the same or lower at the time of follow-up (the PA non-increase group). RESULTS: There were no significant changes in all blood and biochemical parameters in the PA non-increase group at the time of follow-up when compared with baseline levels. In the PA increase group, aspartate aminotransferase, alanine aminotransferase, and γ-guanosine triphosphate levels were all significantly lower at follow-up than they were at baseline. Body weight did not change significantly from baseline to follow-up in both groups. CONCLUSIONS: In the present study, hepatic inflammation improvement was accompanied by increased PA but not decreased body weight. Increasing PA may be effective for the improvement of hepatic inflammation even without body weight loss. Our results indicate the effectiveness of PA monitoring for the management of NAFLD. TRIAL REGISTRATION UMIN-CTR, UMIN000038530.
Activities of Daily Living ; Adult ; Aged ; Aged, 80 and over ; Body Weight ; Exercise ; Female ; Hepatitis ; etiology ; physiopathology ; Humans ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease ; complications ; Weight Loss ; Young Adult

Nonalcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. Immunoglobulin G (IgG) N-glycans are associated with risk factors for NAFLD, such as obesity and diabetes. A cross-sectional study involving 500 Han Chinese adults recruited from a community in Beijing was carried out to explore the association between IgG N-glycans and NAFLD. IgG N-glycosylation was significantly associated with NAFLD, with the disease showing a negative correlation with galactosylation (GP14, GP14n, and G2n), positive correlation with fucosylation (FBG2n/G2n), and positive correlation with bisecting N-acetylglucosamine (GlcNAc) [FBG2n/FG2n and FBG2n/(FG2n+FBG2n)], after controlling age, gender, and prevalence of obesity, type 2 diabetes mellitus, hypertension, and hyperlipidemia. In other words, the present study showed a possible association between NAFLD and the loss of galactose and elevations of fucose and bisecting GlcNAc. Aberrant IgG glycosylation might therefore be a potential biomarker for the primary or secondary prevention of NAFLD.
Biomarkers ; blood ; China ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2 ; blood ; complications ; Female ; Glycosylation ; Humans ; Immunoglobulin G ; blood ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease ; blood ; etiology ; Obesity ; blood ; complications ; Odds Ratio ; Polysaccharides ; blood ; Risk Factors

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.
Adipose Tissue ; pathology ; Animals ; Extracellular Vesicles ; metabolism ; Humans ; Hypothalamus ; metabolism ; Intestines ; microbiology ; pathology ; Non-alcoholic Fatty Liver Disease ; etiology ; metabolism ; microbiology ; pathology

OBJECTIVE: To investigate the effects of sera from rats fed with tablets (HGT) on endoplasmic reticulum (ER) stress in a steatotic hepatocyte model of free fatty acids (FFAs)-induced nonalcoholic fatty liver disease (NAFLD) and explore the possible mechanism. METHODS: FFAs prepared by mixing oleic acid and palmitic acid at the ratio of 2:1. HepG2 cells were treated with the sera from rats fed with low-, moderate-or high-dose HGT (HGT sera) or sera of rats fed with fenofibrate (fenofibrate sera), followed by treatment with 1 mmol/L FFAs for 24 h to induce hepatic steatosis. Oil red O staining was used to observe the distribution of lipid droplets in the cells. The biochemical parameters including triglyceride (TG), lactated hydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using a commercial kit. The morphological changes of the ER in the cells were observed using transmission electron microscopy. The protein/mRNA expressions of ER stress-related signal molecules including GRP78, PERK, p-PERK, ATF6, ATF4, CASPASE-12, CHOP, XBP-1, PKC, and p-PKC-δ were detected using Western blotting and/or quantitative real-time PCR (qRT-PCR). The changes in the protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP were also detected in cells with transient transfection of PKC-δ siRNA for PKC-δ knockdown. RESULTS: Compared with the control cells, the cells treated with FFAs showed significantly increased levels of TG, AST, and ALT ( < 0.05). Compared with FFAs-treated cells, the cells pretreated with HGT sera or fenofibrate sera all showed significantly decreased TG, AST and ALT levels ( < 0.05), reduced accumulation of the lipid droplets ( < 0.05), and lowered protein or mRNA expression levels of GRP78, p-PERK, ATF6, ATF4, CHOP, CASPASE-12, XBP-1 and p-PKC-δ ( < 0.05). PKC-δ knockdown caused significantly reduced protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP in the cells with FFA-induced hepatic steatosis ( < 0.001); treatment with high-dose HGT serum more significantly reduced the expressions of GRP78 ( < 0.001) and P-PERK ( < 0.01) in FFAs-induced cells with PKC-δ knockdown. CONCLUSIONS HGT serum can effectively prevent FFAs-induced steatosis in HepG2 cells by alleviating ER stress, in which PKC-δ may act as an important target.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Endoplasmic Reticulum ; ultrastructure ; Endoplasmic Reticulum Stress ; drug effects ; Fatty Acids, Nonesterified ; Fenofibrate ; administration & dosage ; Hep G2 Cells ; Humans ; Hypolipidemic Agents ; administration & dosage ; Microscopy, Electron, Transmission ; Non-alcoholic Fatty Liver Disease ; blood ; etiology ; prevention & control ; RNA, Messenger ; blood ; Rats ; Serum ; Tablets ; Triglycerides ; blood