The role of complement in nonalcoholic fatty liver disease

Guo, Zhenya; Fan, Xiude; Yao, Jianni; Tomlinson, Stephen; Yuan, Guandou; He, Songqing

doi:10.3389/fimmu.2022.1017467

Cited by 18 publications

(11 citation statements)

References 82 publications

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“…However, one of the main immune pathways that was upregulated following VSG was the complement system. This was surprising as increased levels of complement proteins have been associated with MASH severity in humans 59 and complement has been shown to increase hepatic de novo lipogenesis, inflammation, and insulin resistance 60 . Additional studies are needed to determine if complement proteins play a role in the response of the MASH liver to VSG due to the limited biological implications that can be drawn from transcriptomic data.…”

Section: Discussionmentioning

confidence: 99%

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Fredrickson,

Florczak,

Barrow

et al. 2023

Preprint

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Immune mechanisms are considered a major contributing factor to the inflammatory process and progression of non-alcoholic steatohepatitis (NASH). Bariatric procedures such as vertical sleeve gastrectomy (VSG) have been shown successful in ameliorating the progression of the disease. Several mechanisms of weight-loss-independent improvements due to bariatric surgery have been proposed including bile acid signaling, gut hormones, intestinal tissue reprogramming, and changes in the gut microbiome. However, whether bariatric surgery ameliorates the progression of NASH through anti-inflammatory mechanisms has not been investigated. To determine the effects of VSG on hepatic inflammation, we fed mice a high-fat high-carbohydrate (HFHC) diet for 12 weeks and assigned them to either VSG or Sham surgeries. Independent from weight loss, VSG resulted in reduced hepatic lipid accumulation and ameliorated NASH as early as 5 weeks after VSG. To profile the gene expression of macrophages in the NASH liver following VSG, we performed single-cell RNA sequencing and identified 18 clusters of monocytes and macrophages with a unique gene expression signature. We found substantial alterations in macrophage subsets in association with VSG-induced reversal of NASH. In particular, hepatic lipid-associated macrophages (LAMs), which are enriched in genes associated with lipid metabolism and collagen degradation, were highly responsive to VSG. Differential gene expression analysis revealed that VSG increased the expression of genes involved in lysosomal activity, antigen presentation, and repression of inflammation in LAMs, suggesting that VSG sustains their protective function. Spatial transcriptomic analysis of human liver sections confirmed the enrichment of LAM genes within periportal regions during NASH and a marked reduction following VSG. To determine a causal role for hepatic LAMs in the restorative process induced by VSG against NASH, we performed VSG in mice deficient for the triggering receptor expressed on myeloid cells 2 (Trem2). TREM2-deficiency ablated the protective effects of VSG against NASH, suggesting that LAMs mediate this reparative process. Mechanistically, Trem2 prevents the inflammatory activation of bone marrow-derived macrophages, in agreement with the anti-inflammatory effects of VSG in LAMs. Overall, our findings suggest that bariatric surgery improves NASH through a reparative process driven by hepatic lipid-associated macrophages.

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Section: Discussionmentioning

confidence: 99%

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Fredrickson,

Florczak,

Barrow

et al. 2023

Preprint

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“…Growing evidence disclosed that cytokines were the key mediators of signal transmission among live cells, which may be critically participated in the pathophysiology of NAFLD by inducing hepatic inflammation, IR and fibrosis ( 60 ). As an essential part of innate immune system, complements and their cleavage products were mostly produced by hepatocytes, which also played a fundamental role in the pathogenesis of NAFLD ( 61 ).…”

Section: Metabolic Organ-secreted Factors In Nafldmentioning

confidence: 99%

“…The complement system is an important part of immunity and inflammation that may be involved in the pathogenesis of NAFLD by modulating IR, hepatic inflammation, and lipid metabolism disorders ( 61 ). Under physiological conditions, a potential balance exists between complement system activation and hepatocyte lipid metabolism, which helps to maintain liver homeostasis.…”

Section: Metabolic Organ-secreted Factors In Nafldmentioning

confidence: 99%

“…Moreover, serum C3 levels were considered as an independent risk factor for NAFLD diagnosis and positively correlated with the prevalence and severity of NAFLD ( 71 ). In addition, recent research elucidated that C3a and C5a had chemotactic and pro-inflammatory properties associated with NAFLD ( 61 ). Together, these findings can provide some evidence for complements as novel therapeutic strategies.…”

Section: Metabolic Organ-secreted Factors In Nafldmentioning

confidence: 99%

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The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease

Sun

et al. 2023

Front. Cardiovasc. Med.

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Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by an excessive accumulation of fat in the liver, which is becoming a major global health problem, affecting about a quarter of the population. In the past decade, mounting studies have found that 25%–40% of NAFLD patients have cardiovascular disease (CVD), and CVD is one of the leading causes of death in these subjects. However, it has not attracted enough awareness and emphasis from clinicians, and the underlying mechanisms of CVD in NAFLD patients remain unclear. Available research reveals that inflammation, insulin resistance, oxidative stress, and glucose and lipid metabolism disorders play indispensable roles in the pathogenesis of CVD in NAFLD. Notably, emerging evidence indicates that metabolic organ-secreted factors, including hepatokines, adipokines, cytokines, extracellular vesicles, and gut-derived factors, are also involved in the occurrence and development of metabolic disease and CVD. Nevertheless, few studies have focused on the role of metabolic organ-secreted factors in NAFLD and CVD. Therefore, in this review, we summarize the relationship between metabolic organ-secreted factors and NAFLD as well as CVD, which is beneficial for clinicians to comprehensive and detailed understanding of the association between both diseases and strengthen management to improve adverse cardiovascular prognosis and survival.

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“…9,10 Recently, there has been growing attention to the role of the complement system in the pathogenesis of NAFLD. [11][12][13] Classically, the complement system is a pivotal component of the innate immune system, playing an essential part in protecting the host from infection and promoting tissue homeostasis and repair. However, once dysregulated in its activity, the complement system has been demonstrated to be involved in a variety of both infectious and non-infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

Nguyen,

Hughes,

Zhou

2023

Liver International

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Non‐alcoholic fatty liver disease (NAFLD) is a growing public health threat and becoming the leading cause of liver transplantation. Nevertheless, no approved specific treatment is currently available for NAFLD. The pathogenesis of NAFLD is multifaceted and not yet fully understood. Accumulating evidence suggests a significant role of the complement system in the development and progression of NAFLD. Here, we provide an overview of the complement system, incorporating the novel concept of complosome, and summarise the up‐to‐date evidence elucidating the association between complement dysregulation and the pathogenesis of NAFLD. In this process, the extracellular complement system is activated through various pathways, thereby directly contributing to, or working together with other immune cells in the disease development and progression. We also introduce the complosome and assess the evidence that implicates its potential influence in NAFLD through its direct impact on hepatocytes or non‐parenchymal liver cells. Additionally, we expound upon how complement system and the complosome may exert their effects in relation with hepatic zonation in NAFLD. Furthermore, we discuss the potential therapeutic implications of targeting the complement system, extracellularly and intracellularly, for NAFLD treatment. Finally, we present future perspectives towards a better understanding of the complement system's contribution to NAFLD.

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The role of complement in nonalcoholic fatty liver disease

Cited by 18 publications

References 82 publications

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

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