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What are most important factors related to Non-alcoholic Fatty Liver?


What are most important factors related to Non-alcoholic Fatty Liver?

“Collector’s Edition” Review of Nature Metabolism︱Metabolism, Gut Microbiota and Immunity: Most three important factors on Nonalcoholic Fatty Liver


Non-alcoholic fatty liver disease ( NAFLD ) is defined as bullous steatosis in more than 5% of liver cells in the absence of secondary causes such as alcohol or drugs.

NAFLD is the most prevalent liver disease globally, affecting approximately 25% of the world’s population, ranging from 13% in Africa to 23% in Europe and 32% in the Middle East.

NAFLD manifests in different phenotypes ranging from simple steatosis to nonalcoholic steatohepatitis ( NASH ) , fibrosis, cirrhosis and even hepatocellular carcinoma. In most NAFLD patients, liver histology shows simple steatosis, whereas up to 30% show inflammation and/or fibrosis.

Patients with NAFLD and simple steatosis, especially those with NASH or liver fibrosis, develop long-term complications (mainly cardiovascular disease and malignancy) that lead to increased mortality.


With the rising incidence of obesity, type 2 diabetes and metabolic syndrome, the incidence of NAFLD is also rising, and NAFLD is expected to become the leading cause of cirrhosis (requiring liver transplantation) in the next 10 years [1,2] .

It is known that NAFLD is a complex systemic disease whose pathophysiology is mainly focused on metabolic dysfunction and lipotoxicity, however, the current public understanding of the disease is still very limited.


On December 20, 2021, Herbert Tilg et al. from the Medical University of Innsbruck, Austria, published a review online in Nature Metabolism entitled Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity , discussing the pathophysiology of NAFLD.

Three cornerstones—metabolic dysfunction, gut microbiome alterations, and innate and adaptive immune dysregulation, while presenting a concept of how metabolic dysbiosis, dysbiosis, and liver-damaging immunity can create a self-amplifying vicious cycle in NAFLD, and how this interaction contributes to the evolution of NASH and complex NAFLD.


What are most important factors related to Non-alcoholic Fatty Liver?



Metabolic Dysfunction and NAFLD


Metabolic dysfunction such as hepatic steatosis is considered an important early step in the pathogenesis of NAFLD.

There is a strong link between NAFLD and type 2 diabetes (T2DM) – more than 70% of people with T2DM have NAFLD and more than 20% of people with NAFLD have or will have T2DM.

Thus, there are many overlapping pathophysiological aspects between NAFLD and T2DM.

Liver fat accumulation, most commonly seen in obese or T2DM patients, is not only the first onset of NAFLD, but toxicity from certain lipids may also drive further progression of the disease, such as inflammation, liver damage, and insulin resistance.

The authors of this paper elaborate on the close link between metabolic dysfunction and NAFLD from three perspectives.


1. Lipid metabolism and glucose metabolism in the liver

Hepatic steatosis is a complex process caused by many causes.

Increased lipid or free fatty acid (FFA) influx into the liver and increased de novo lipid synthesis (DNL) (often associated with hepatic insulin resistance) play a key role in this, while reduced fatty acid oxidation and hepatic lipid output (among other mechanism) may also work.

At the same time, since fructose is mainly metabolized to triglycerides by DNL, ​​there is no doubt that excessive intake of fats and carbohydrates (especially fructose) plays a non-negligible role in the etiology of NAFLD.


2. Lipotoxicity and liver damage

Lipids have long been thought to be hepatotoxic and to propagate inflammatory responses.

Although triglycerides have long been considered the main culprit in lipotoxicity, recent evidence suggests that cholesterol and sphingomyelin (SM) are equally involved in lipid-induced liver inflammation.

While most lipids accumulate in steatotic liver as inert triglycerides, some lipids, such as saturated fatty acids, diacylglycerols, ceramides, free cholesterol (FC), or SM, are lipotoxic.

Nucleotide oligomeric domain-containing protein (NOD) -, LRR-, and pyran domain-containing protein (NLRP) 3 inflammasomes link lipid sensing to induction of inflammation and have been shown to play a role in obesity and related diseases effect.

It is worth mentioning that although the concept of lipotoxicity is strongly confirmed in NAFLD (Figure 1) , 70–80% of NAFLD patients never develop steatotic liver inflammation, suggesting host genes and possibly specific dietary lipids. Play a protective or anti-inflammatory function.


In addition to causing inflammasome activation and oxidative stress, lipotoxic lipids also disrupt ER functions, such as lipid homeostasis.

Endoplasmic reticulum dysfunction, collectively referred to as endoplasmic reticulum stress, orchestrates key cell signaling events in obesity, type 2 diabetes, and liver disease, and has been progressively demonstrated to have a role in human NAFLD.


3. Insulin resistance

Insulin resistance has been identified as a key feature of NAFLD, although the current chicken-and-egg question remains unresolved and whether hepatic steatosis occurs prior to insulin resistance or whether insulin resistance leads to hepatic steatosis remains unclear. 

Hepatic insulin resistance—impaired insulin’s ability to suppress hepatic glucose production—is present in the majority of NAFLD patients and is important evidence that NAFLD constitutes a systemic metabolic disorder.

The pathophysiological basis of hepatic insulin resistance is very complex. On the one hand, various lipids are key drivers of systemic and tissue-specific insulin resistance.

On the other hand, tissue inflammation also affects insulin resistance.

In conclusion, a complex interplay of non-inflammatory and inflammatory components may contribute to hepatic and systemic insulin resistance in NAFLD patients.


What are most important factors related to Non-alcoholic Fatty Liver?Figure 1 Metabolic disorders and NAFLD




Gut dysbiosis and NAFLD


There is increasing evidence that the gut microbiota-liver axis plays a key role in NAFLD, especially in the progression to more advanced disease.

Numerous preclinical models and well-powered human studies have demonstrated altered microbiota in patients with NAFLD.

The underlying mechanism of gut microbiota affecting fatty liver disease is driven by the metabolites of gut microbiota on the one hand, and bacterial endotoxins on the other hand.

In addition, with the deepening of research, the role of bile acids in NAFLD has received increasing attention, and NAFLD patients exhibit elevated serum bile acid concentrations in both fasting and postprandial serum, which are associated with more severe liver disease and are associated with insulin resistance, But not with liver inflammation.

At the same time, clinical trials have shown that obeticholic acid or 24-deoxycholic acid can improve the symptoms of NAFLD, and it has also confirmed that bile acids play a key role in NAFLD.

Of course, despite a growing body of preclinical and clinical studies demonstrating a role for gut dysbiosis in NAFLD, which strains (or lack of strains) may drive some of the key features of the disease, such as hepatic steatosis, inflammation , liver injury or the process of insulin resistance remains to be further elucidated.



Immune Dysregulation and NAFLD


A growing number of studies have found that both innate and adaptive immunity are closely related to metabolic disorders such as NAFLD .


1. Innate immunity drives metabolic inflammation

Sterile inflammation during NAFLD is thought to be triggered by the innate immune system, which is critical in NAFLD. Many immunometabolic disorders, such as NAFLD, are characterized by intermittent chronic low-grade inflammation (called “metabolic inflammation”) .

Scientists have proposed more than a decade ago that liver inflammation may be caused by various signals from the gastrointestinal tract (microbes and/or diet) and adipose tissue (lipids, cytokines) .

Growing evidence suggests that the level of physical activity, the stability of the gut microbiota, dietary factors, and certain lipid concentrations or combinations may be major contributors to chronic inflammation in NAFLD.

Especially in obesity and obesity-related diseases, adipose tissue has become a major source of circulating proinflammatory cytokines, thereby affecting the degree of liver inflammation.


Cytokines and related mediators, mainly derived from immune cells, play an important role in any inflammatory state, and pro-inflammatory cytokines have been shown to be highly expressed in NAFLD , especially NASH .

Notably, the inflammation-promoting mechanism of NAFLD may be the result of specific molecular processes rather than nonspecific activation of cytokines. Furthermore, NLRP3 and various Toll-like receptors (TLRs) affect key pathways in NAFLD, including inflammatory infiltration of liver and adipose tissue and regulation of insulin sensitivity.

In fact, modulation of gut microbiota through the activity of certain TLRs or inflammatory mediators may lead to changes in associated inflammation, which in turn may exacerbate hepatic inflammation and NAFLD.

Thus, a combination of innate immunity, altered microbial composition, increased gut microbial translocation, and cellular innate immune sensing pathways may all contribute to the establishment of chronic inflammation in the liver.


2. Adaptive immunity in NAFLD

Adaptive immunity helps control pathogen-infected or transformed cells in cancer, primarily through effector function through the killing of their target cells by specific CD8+ T cells, and understanding the regulation of adaptive immunity in the context of NAFLD has become increasingly important. much attention.

Unlike the sterile inflammation of NAFLD described above, chronic infectious liver inflammation is the destruction of liver tissue by adaptive immunity targeting virally infected hepatocytes during chronic hepatitis B, C, or D.

Consistent with the role of adaptive immunity in NAFLD, an increase in the number of antigen-presenting cells correlates with the severity of NASH.

Furthermore, although there is little evidence for recognition of self-antigens or T-cell autoimmunity, it is now clear that metabolic activation of liver-resident T cells is a key factor in NASH histopathology, yet it remains unclear how T cells contribute to NAFLD of liver damage.

Certainly, identifying self-aggressive T cells (whose activation differs from the T cells that protect us from infection and cancer) as drivers of NAFLD liver injury and liver cancer will help identify molecular targets for intervention at the level of immune-mediated liver injury .


Taken together, there are multiple interactions between metabolic pathways, gut microbiota, and immunity in NAFLD, and it would be unwise to characterize any one factor in isolation.

Collectively, metabolic dysregulation, dietary factors, obesity, and T2DM can alter gut microbiota that act as a pool of metabolites and inflammatory signaling in patients with and without leaky gut Originated signals challenge the sterile nature of liver disease by harnessing pattern recognition receptors and metabolic reprogramming to direct innate and adaptive immune responses.

This complex “triangle of NAFLD” suggests that late stages of the disease may be driven by immune dysregulation, gut imbalance, and metabolic disturbances, which together promote hepatic inflammation and other aspects of NAFLD (Figure 2) .


What are most important factors related to Non-alcoholic Fatty Liver?Figure 2 Interactions between metabolism, gut microbiota and immunity in NAFLD







1. Diehl, AM & Day, C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072 (2017).

2. James, M., Pinelopi, M. Non-alcoholic fatty liver disease. Clin Med (Lond). 18(3):245-250 (2018).

What are most important factors related to Non-alcoholic Fatty Liver?

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