Diet and nonalcoholic fatty liver disease

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a common and serious form of chronic liver disease. It is characterized by lipid accumulation in the liver and is associated with all aspects - and may even be an initiating factor - of the metabolic syndrome. The purpose of this review is to summarize recent findings from human studies on dietary effects on hepatic lipid accumulation. RECENT FINDINGS: Epidemiological studies did not give consistent results. From intervention studies there is evidence to support a role for weight loss. Some studies have also suggested that decreasing total fat intake and increasing the intake of fish oils may be beneficial in the treatment of nonalcoholic steatohepatitis. SUMMARY: Only a few studies have focused on dietary effects on hepatic lipid accumulation. So far, there is only evidence to support a role for weight loss. Decreasing total fat intake and increasing the intake of fish oils may also be beneficial, but these conclusions are based on a limited number of studies, which sometimes lacked a proper control group. Also, other nutrients have not been studied in detail. Therefore, there is an urgent need for evidence-based dietary guidelines to prevent or even to treat nonalcoholic fatty liver disease.     

The hedgehog pathway in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hh pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.     

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. RECENT FINDINGS: Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. SUMMARY: Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.     

Modulation of endoplasmic reticulum stress via sulforaphane-mediated AMPK upregulation against nonalcoholic fatty liver disease in rats

Nonalcoholic fatty liver disease (NAFLD) is a major health concern. Endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may be targeted to prevent the progress of nonalcoholic fatty liver disease. Sulforaphane (SFN), a sulfur-containing compound that is abundant in broccoli florets, seeds, and sprouts, has been reported to have beneficial effects on attenuating metabolic diseases. In light of this, the present study was designed to elucidate the mechanisms by which SFN ameliorated ER stress, inflammation, lipid metabolism, and insulin resistance — induced by a high-fat diet and ionizing radiation (IR) in rats. In our study, the rats were randomly divided into five groups: control, HFD, HFD + SFN, HFD + IR, and HFD + IR + SFN groups. After the last administration of SFN, liver and blood samples were taken. As a result, the lipid profile, liver enzymes, glucose, insulin, IL-1β, adipokines (leptin and resistin), and PI3K/AKT protein levels, as well as the mRNA gene expression of ER stress markers (IRE-1, sXBP-1, PERK, ATF4, and CHOP), fatty acid synthase (FAS), peroxisome proliferator–activated receptor-α (PPAR-α). Interestingly, SFN treatment modulated the levels of proinflammatory cytokine including IL-1β, metabolic indices (lipid profile, glucose, insulin, and adipokines), and ER stress markers in HFD and HFD + IR groups. SFN also increases the expression of PPAR-α and AMPK genes in the livers of HFD and HFD + IR groups. Meanwhile, the gene expression of FAS and CHOP was significantly attenuated in the SFN-treated groups. Our results clearly show that SFN inhibits liver toxicity induced by HFD and IR by ameliorating the ER stress events in the liver tissue through the upregulation of AMPK and PPAR-α accompanied by downregulation of FAS and CHOP gene expression.     

Anti-inflammatory activities of green tea catechins along the gut–liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies

Nonalcoholic fatty liver disease (NAFLD), which is the most prevalent hepatic disorder worldwide, affecting 25% of the general population, describes a spectrum of progressive liver conditions ranging from relatively benign liver steatosis and advancing to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Hallmark features of NASH are fatty hepatocytes and inflammatory cell infiltrates in association with increased activation of hepatic nuclear factor kappa-B (NFκB) that exacerbates liver injury. Because no pharmacological treatments exist for NAFLD, emphasis has been placed on dietary approaches to manage NASH risk. Anti-inflammatory bioactivities of catechin-rich green tea extract (GTE) have been well-studied, especially in preclinical models that have detailed its effects on inflammatory responses downstream of NFκB activation. This review will therefore discuss the experimental evidence that has advanced an understanding of the mechanisms by which GTE, either directly through its catechins or potentially indirectly through microbiota-derived metabolites, limits NFκB activation and NASH-associated liver injury. Specifically, it will describe the hepatic-level benefits of GTE that attenuate intracellular redox distress and pro-inflammatory signaling from extracellular receptors that otherwise activate NFκB. In addition, it will discuss the anti-inflammatory activities of GTE on gut barrier function as well as prebiotic and antimicrobial effects on gut microbial ecology that help to limit the translocation of gut-derived endotoxins (e.g. lipopolysaccharides) to the liver where they otherwise upregulate NFκB activation by Toll-like receptor-4 signaling. This summary is therefore expected to advance research translation of the hepatic- and intestinal-level benefits of GTE and its catechins to help manage NAFLD-associated morbidity.     

Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning public health concern in westernized nations. The obesity-related disorder is associated with an increased risk of cardiovascular disease, type 2 diabetes and liver failure. Although the underlying pathogenesis of NAFLD is unclear, increasing evidence suggests that excess saturated fatty acids presented to or stored within the liver may play a role in both the development and progression of the disorder. A putative mechanism linking saturated fatty acids to NAFLD may be endoplasmic reticulum (ER) stress. Specifically, excess saturated fatty acids may induce an ER stress response that, if left unabated, can activate stress signaling pathways, cause hepatocyte cell death, and eventually lead to liver dysfunction. In the current review we discuss the involvement of saturated fatty acids in the pathogenesis of NAFLD with particular emphasis on the role of ER stress.     

The role of fatty acids in the development and progression of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a serious obesity-related disorder. NAFLD encompasses a wide spectrum of hepatic derangements ranging from a surfeit of fat in the liver (steatosis) to lipid surplus accompanied by fibrosis and cellular death (nonalcoholic steatohepatitis or NASH). The most widely accepted model to explain the progression from simple NAFLD to NASH is the "two-hit hypothesis," wherein fat over accumulation per se is not sufficient to induce the progression to statohepatitis, but renders the liver more susceptible to "second hits" that, once imposed upon the steatotic liver, cause further aberrations that culminate in the development of NASH. However, in light of recent data from our laboratory and elsewhere, we propose that an increased ratio of saturated-to-unsaturated fatty acids delivered to or stored within the liver may, in part, mediate the progression from simple steatosis to NASH. The molecular mechanisms that mediate the effect of saturated fatty acids are unclear, although proinflammatory cytokines, reactive oxygen species, and endoplasmic reticulum stress may all play a role. Collectively, these data suggest that saturated fatty acids may represent an intrinsic second hit to the liver that hastens the development of NASH.     

Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to define the circulating profile of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels reflect histological changes in the liver. The levels of multiple structurally specific oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9- and 13-HODEs and 9- and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were significantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (inflammation, fibrosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold (P < 0.0001) more likely to have NASH than those with low levels (bottom tertile). Collectively, these findings support a key role for free radical-mediated linoleic acid oxidation in human NASH and define a risk score, oxNASH, for noninvasive detection of the presence of NASH.     

芳香烃受体在非酒精性脂肪性肝脏疾病中的作用

非酒精性脂肪性肝脏疾病(nonalcoholic fatty liver diseases,NAFLD)是目前备受关注的一种肝脏疾病。肥胖、2型糖尿病、高脂血症等是NAFLD的重要危险因素,但其发病机理仍不十分清楚。芳香烃受体(aryl hydrocarbon receptor,AHR)是由配体激活的转录因子,其在多种重要疾病活动中发挥了重要作用。近年来多项研究表明AHR激活促进了NAFLD的发病进展,对AHR参与NAFLD发病机制的探讨将有利于进一步阐明NAFLD的发病机理,为NAFLD的防治提出新的思路。本文就AHR与NAFLD关系的研究进展做一综述,以期为该领域的研究提供新的方向。     

益生菌改善非酒精性脂肪肝病的研究进展

非酒精性脂肪肝病(non alcoholic fatty liver disease,NAFLD)是一种较为常见的慢性肝病,在我国居民中NAFLD正呈现低龄化和迅速上升的态势。而NAFLD的发病机制尚未完全阐明,一般认为其与肥胖、糖尿病、高脂血症、胰岛素抵抗及遗传易感等诸多因素相关。“肠-肝轴”学说的提出,使医药界同仁普遍认识到肠道益生菌在NAFLD的发生过程中扮演着重要角色,也随之引发了关于肠道益生菌对NAFLD治疗价值的思考与探索。该综述主要对益生菌改善NAFLD的研究进展进行总结,以期能够为NAFLD临床治疗提供参考。     

Serum lipocalin-2, cathepsin S and chemerin levels and nonalcoholic fatty liver disease

Several novel circulating adipokines are associated with insulin resistance and inflammation. Little information exists in NAFLD about three recently recognized adipokines lipocalin-2, cathepsin S and chemerin. To assess the relationship between serum lipocalin-2, cathepsin S and chemerin levels and the development of non-alcoholic fatty liver in Chinese subjects, we measured serum lipocalin-2, cathepsin S and chemerin levels in 903 Chinese subjects by ELISA. Among the study population, 436 patients are with B-mode ultrasound-proven NAFLD and 467 controls. Levels of lipocalin-2, but not cathepsin S and chemerin, were significantly elevated in NAFLD versus control [lipocalin-2, 89.67 ± 4.47 vs. 68.70 ± 3.65 ng/mL (p < 0.001)]. After stepwise linear regression analysis adjusting for potential cofounders, further revealed that serum lipocalcin-2 was an independent predictor of NAFLD in whole cohort (standardized β = 0.114, t = 2.347, p = 0.02). Lipocalin-2 levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) and inflammation (CRP) in whole cohorts and NAFLD, whereas cathepsin S and chemerin only correlated positively with insulin resistance and inflammation in whole cohorts. Our results indicated that circulating lipocalin-2, produced by adipocytes, are elevated and may contribute to the development of NAFLD. Serum lipocalin-2, which correlates with inflammation and insulin resistance, may have a direct pathogenic link to disease progression.     

Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo‐controlled 10‐week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.     

Free radical biology for medicine: learning from nonalcoholic fatty liver disease

Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.     

Working hours and nonalcoholic fatty liver disease according to sleep duration

ABSTRACT

There is no study on the relationship between working hours and nonalcoholic fatty liver disease (NAFLD). The objective of the present study was to determine the relationship between working hours and NAFLD by sleep duration using a large set of abdominal ultrasonography examination data. Data from 194,625 patients who underwent health examinations from 2015 to 2017 were analyzed. Chi-square tests, linear-by-linear association and ANOVA were performed to compare general characteristics according to working hours. Multivariate logistic regression analysis was performed to determine the relationship between working hours and NAFLD by sleep duration. There was no significant relationship between working hours and NAFLD prevalence in the group of short sleep duration of ≤5 hours or the group of long sleep duration of ≥7 hours. The risk of NAFLD in the >52 working hour group was significantly higher (aOR, 1.09; 95% CI, 1.04–1.14) than that in the 40- to 52-hour working hour group after adjusting for confounding factors in the 5- to 6-hour sleep duration group. There was no significant difference between ≤40 working hours and 40 ~ 52 working hours in the 5 ~ 6 hours sleep duration group (aOR, 1.02; 95% CI, 0.97–1.06). In general, working hours were significantly related to NAFLD. There was a difference in the relationship between working hours and NAFLD according to sleep duration.