Nonalcoholic Fatty Liver Disease and Its Treatment

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1		HUANG Wenwu	--	1830	2023-10-10 09:08:27	\|
2	references update	Fanny Huang	-1 word(s)	1829	2023-10-13 07:34:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/foods12183393

Non-alcoholic fatty liver disease, commonly abbreviated to NAFLD, is a pervasive ailment within the digestive system, exhibiting a rising prevalence, and impacting individuals at increasingly younger ages. Studies have shown that synbiotics, which regulate intestinal microecology, can positively impact glucolipid metabolism, and improve NAFLD-related indicators. Sonchus brachyotus DC., a Chinese herb, exhibits hepatoprotective and potent antioxidant properties, suggesting its potential therapeutic use in NAFLD. Our preclinical animal model investigation suggests that the synergy between Sonchus brachyotus DC. extracts and synbiotics is significantly more effective in preventing and treating NAFLD, compared to the isolated use of either component. As a result, this combination holds the potential to introduce a fresh and encouraging therapeutic approach to addressing NAFLD.

NAFLD synbiotics

1. Introduction

NAFLD is a clinicopathological condition characterized by hepatic steatosis and lipid accumulation. It serves as a prominent underlying factor for chronic liver diseases, carrying a notable risk of liver fibrosis, which can occur in up to 25% of cases ^[1]. NAFLD, often correlated with metabolic syndrome and type 2 diabetes mellitus (T2DM), fosters the progression of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and extrahepatic cancers. Consequently, cardiovascular ailments, malignant tumors, and advanced liver conditions are the chief contributors to mortality in individuals afflicted by NAFLD.

In recent years, the prevalence of NAFLD has continued to rise, due to improved material living standards and dietary changes. Presently, non-alcoholic fatty liver disease (NAFLD) stands as one of the most widespread chronic liver conditions globally. It affects roughly 30% of adults, constituting a substantial fraction of the hepatic-related morbidity and mortality ^[2]. In 2018, the global prevalence of NAFLD was estimated at 25%, with 27.37% of cases in Asia. Modeling studies project a continuous 30% increase in fatty liver disease worldwide by 2030 compared to previous years in eight countries, including China, the UK, France, and Germany ^[3]^[4]. This alarming trend, with the NAFLD prevalence in China rising from 13% to 43% over the last 20 years ^[5], signifies a growing burden on individuals and society. Currently, there are no approved therapies for NAFLD, except for weight loss through various interventions to slow the disease progression. Current treatments focus on improving insulin sensitivity, and reducing liver enzyme levels through lifestyle changes and medications. However, these interventions lack comprehensiveness and effectiveness in alleviating NAFLD. The side effects and long-term administration of insulin sensitizers and vitamin E may limit their widespread acceptance ^[6]. Although dietary intervention and exercise are recommended as first-line therapies, they are often required in combination with pharmacological or surgical treatments for disease improvement, which are not entirely effective. Consequently, the lack of an efficient therapy for NAFLD continues to be a significant problem in healthcare. The current NAFLD research aims to develop single-agent and effective therapies to improve patient compliance.

As the research on intestinal microecology advances rapidly, probiotics and prebiotics have attracted increasing interest among researchers, due to their regulatory functions in the gut. Synbiotics, a synergistic blend of probiotics and prebiotics, offer an indirect yet profound advantage to human wellbeing. They operate by fostering the growth of advantageous gut microbiota, and overseeing their metabolic processes. This intricate interplay culminates in a fortified immunity, and refined metabolic equilibrium. Moreover, synbiotics have been found to improve blood glucose and insulin levels ^[7], which aligns with the prevailing view that NAFLD has a connection with metabolic levels and insulin resistance. This suggests the potential efficacy of synbiotics in treating NAFLD and related disorders.

2. Nonalcoholic Fatty Liver Disease and Its Treatment

2.1. Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver metabolic syndrome characterized by an abnormal metabolism and excessive lipid accumulation, resulting in steatosis in over 5% of liver cells ^[8]. While its pathological alterations bear a resemblance to alcoholic liver disease, NAFLD manifests in individuals who do not have a history of significant alcohol intake. It is frequently associated with metabolically abnormal obesity, featuring dyslipidemia and hyperglycemia. NAFLD is a leading cause of chronic liver diseases, progressing to nonalcoholic steatohepatitis (NASH), cirrhosis, and complications such as an abnormal glucose tolerance, hypertension, hyperviscosity, and coronary heart disease. Additionally, NAFLD has a close connection with the development of hepatocellular carcinoma ^[9]. Recent studies have introduced the term metabolic dysfunction-associated fatty liver disease (MAFLD) to encompass NAFLD, expanding its pathology classification, and explicitly associating it with type 2 diabetes and metabolic dysfunction. This redefinition opens up new avenues for future NAFLD treatment ^[10]^[11].

2.2. The Pathogenesis of NAFLD

The pathogenesis of NAFLD is still not understood. Petersen et al. ^[12] suggest that NAFLD results from an overabundance of triglyceride accumulation in the liver due to an energy surplus, which is consistent with the higher prevalence of NAFLD in obese individuals. The liver accumulates lipids by absorbing fatty acids released from peripheral adipose tissue and ingested orally. Skeletal muscle insulin resistance leads to excessive hepatic fat accumulation via the shifting of glucose from skeletal muscle glycogen synthesis to de novo lipid synthesis ^[13]. Consequently, hepatic insulin resistance hinders the function of glycogen synthase, redirecting glucose into lipogenic processes, and promoting NAFLD. Studies using mice lacking hepatic glycogen synthase have shown increased hepatic adipogenesis and NAFLD development due to hepatic insulin resistance ^[14]. In conclusion, insulin resistance promotes excessive fatty acid intake and de novo lipogenesis in the liver, ultimately leading to hepatocyte dysfunction and NAFLD development.

The “second hit” theory, first proposed internationally in 1998, has gained wide acceptance ^[14]. It suggests that unhealthy lifestyles and dietary habits lead to lipid accumulation in the liver, causing hepatocyte steatosis and sustained cellular damage (“first hit”). This damage triggers the secretion of inflammatory cytokines, contributing to mitochondrial dysfunction, oxidative stress, and massive liver cell death, ultimately resulting in hepatocyte damage and steatohepatitis (“second hit”) (Figure 1). The emergence of NAFLD is intricately linked to heightened oxidative stress, an undue accumulation of lipids within the liver, and inflammatory processes. Research has elucidated that disruptions in lipid metabolism lead to the buildup of hepatic lipids, thereby exerting a profound impact on the generation of various reactive oxygen species (ROS). These sources of ROS span from mitochondria and the endoplasmic reticulum (ER) to NADPH oxidase, contributing to the oxidative milieu within the liver. NAFLD results in excessive mitochondrial ROS production in the liver, and increased ROS generation is involved in the regulation of insulin signaling and lipid-metabolism-related enzyme expression and activity, further promoting NAFLD development ^[15]. The redox signaling pathway interacts with the immune signaling network to regulate the inflammatory response. Consequently, the pathogenic progression of NAFLD is extremely intricate, prompting the formulation of the “multiple hit” theory to elucidate its developmental mechanisms ^[16].

Figure 1. The second-hit pathogenesis of NAFLD. A genetic predisposition coupled with an unhealthy diet leads to an excessive accumulation of fatty acids in the liver. Concurrently, the heightened insulin resistance in the adipose tissue initiates an inflammatory response, prompting the release of adipocytokines. These cytokines activate hepatic stellate cells, initiating a cascade that culminates in hepatic fibrosis and fatty liver, constituting the “first hit”. Subsequently, this sets the stage for persistent hepatocyte damage, stress responses, and hepatocyte apoptosis, collectively manifesting as liver hepatitis, or the “second hit”.

Although the exact pathogenesis of NAFLD remains enigmatic, there is a consensus regarding its substantial correlation with metabolic disorders and insulin resistance. This connection is substantiated by the “second hit” and “multiple hit” theories, along with the corresponding empirical findings ^[17]^[18]. Amongst the two theories, the former garners greater acceptance. This theory posits that, subsequent to hepatocytes undergoing the initial impact, insulin resistance and leptin resistance ensue, culminating in hepatic steatosis. This process, in turn, triggers inflammation, necrosis, and fibrosis as a response to oxidative stress. This highlights the role of an abnormal endocrine axis function in NAFLD development. These findings may provide new directions for the development of drugs or functional foods to treat NAFLD, with the goal of improving insulin resistance, and preventing the second blow to hepatocytes from oxidative stress, thus preventing the development of hepatocellular carcinoma, cirrhosis, and complications.

2.3. The Treatment for NAFLD

Ganesh et al. ^[6] summarized the current global treatment options and recommendations for NAFLD in their review. Currently, there are no approved treatments for NAFLD, and weight loss interventions may be the most effective approach. Pharmacological interventions for NAFLD primarily seek to enhance insulin sensitivity, while reducing hepatic inflammation and fibrosis biomarkers. An ongoing study in the United States for NASH treatment has shown that omega-3 fatty acid esters (eicosapentaenoic acid) may be a potential candidate for the first-line treatment of hypertriglyceridemia in NAFLD patients. Certain studies propose that polyunsaturated fatty acids (PUFAs) play a pivotal role in enhancing hepatic steatosis and the biochemical markers associated with non-alcoholic fatty liver disease (NAFLD), while also improving insulin sensitivity, and mitigating inflammation ^[19]^[20]. However, another study indicated that PUFA did not have disease-modifying effects in NASH patients with diabetes ^[21], suggesting certain limitations in its use for these patients. Further research is required to determine the optimal dosage of omega-3 PUFA supplementation, and its effects on hepatic lipids.

Insulin sensitizers, extensively evaluated and recognized in previous treatment studies for NASH, have shown promising results. For instance, pioglitazone, a trial drug, has demonstrated an improvement in steatohepatitis, compared to vitamin E and the placebo ^[22]. Long-term pioglitazone treatment resulted in significant improvements in liver damage. However, long-term administration may carry the risks of cardiovascular disease and bone loss ^[23]^[24]^[25]^[26]^[27]^[28]. Metformin, commonly used to treat type 2 diabetes, also improves NAFLD, by increasing glucose utilization in the peripheral tissues. Studies have demonstrated that metformin improves insulin sensitivity, liver histology, and serum alanine transaminase (ALT) levels, particularly in obese NASH patients ^[29]. Vitamin E, a lipophilic antioxidant, has been shown to slow down the progression of NAFLD, by effectively reducing oxidative damage, and inhibiting inflammatory cytokine production in the liver ^[22]^[30]. Clinical trials have revealed that, after 96 weeks of treatment, a notable 43% of all participants exhibited marked histological enhancements. These improvements were particularly pronounced in relation to the amelioration of inflammation in both the hepatocyte ballooning and lobular areas. These positive changes can be largely attributed to a reduction in oxidative stress-induced damage ^[31].

Probiotics have also been mentioned in treatment protocols, and have shown potential benefits in NAFLD treatment. In a review published in 2021, Yao et al. ^[32] analyzed the application of intestinal flora in NAFLD treatment, specifically highlighting the positive effects of Lactobacillus plantarum in reducing ALT and AST levels in patients. The use of active ingredients from Chinese herbal medicine, following the discovery of artemisinin for the treatment of malaria, has gained increasing attention. Traditional Chinese medicine often refers to fatty liver as “liver accumulation” and “liver gangrene”, and several herbs, such as Rhizoma Coptidis (Huang Lian), Radix Salvia Miltiorrhizae (Dan Shen), Rhei Rhizoma (Da Huang), Fructus Gardeniae (Zhi Zi), and Semen Cassiae (Jue Ming Zi), are commonly used in NAFLD treatment, due to their natural ingredients that can reverse steatosis, regulate blood lipids, inhibit inflammation, and resist oxidative stress. Studies have shown the therapeutic effects of Radix Salvia Miltiorrhizae extract salvia phenolic acid B, Semen Cassiae, and Fructus Gardeniae extracts in NAFLD via the inhibition of inflammation, and anti-oxidative stress ^[33]^[34]^[35]. These findings provide valuable insights into, and theoretical support for, combining synbiotics with active ingredients from herbal medicines in NAFLD treatment.

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