Navigating the complex landscape of non‐alcoholic fatty liver disease: From genomic associate to the AMPK/mTOR pathways
Year: 2023
Type: article
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases from steatosis (fat accumulation in hepatocytes) to non-alcoholic steatohepatitis (NASH), which may further progress to cirrhosis and hepatocellular carcinoma (HCC). Although no consensus is achieved regarding the change in the terminology “NAFLD” to metabolic-associated fatty liver disease,1 NAFLD is known for its association with the epidemic of obesity, type 2 diabetes, and metabolic disorders. As the global prevalence of NAFLD continues to rise, it is critical to better understand its pathogenesis and progression. In the current JGH issue, we have published two reviews to discuss the research progress and perspective in the field. Marcondes-de-Castro et al. highlighted the significance of the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway in healthy liver and NAFLD.2 Tian and Wang3 reviewed the pathogenesis of NAFLD through genome-wide association studies. Investigating the underlying mechanisms, such as the AMPK/mTOR pathway and genomic data, will likely identify new biomarkers for diagnostic and therapeutic strategies for NAFLD and its progression to steatohepatitis, cirrhosis, and HCC. Activation of AMPK enhances fatty acid oxidation, promotes glucose uptake, and inhibits lipid synthesis whereas mTOR (including complexes mTORC1 and mTORC2) promotes anabolic processes, such as protein synthesis and cell growth, especially mTOR complex 1 in liver. The balance of AMPK/mTOR is essential for the liver homeostasis. Targeting these pathways, such as metformin (an AMPK activator) and rapamycin (an mTOR inhibitor), have shown potential in experimental models of NAFLD. The mTORC1 signaling in lipid metabolism helps lipogenesis inhibit liver lipophagy, sometimes in concurrence with or antagonistic to AMPK. In their paper, Marcondes-de-Castro et al. summarized the key regulators of AMPK/mTOR pathways in the healthy liver.2 They discussed the role of inflammation and autophagy in NAFLD. They agreed that mitochondrial dysfunction and augmented autophagy and mitophagy in NAFLD attempt to save cells from apoptosis.2 The mechanisms of mitophagy in various liver diseases were discussed in a reviewer by Ma et al.4 for readers' further reference. Significant understanding has been made in the pathogenesis of NAFLD. It is known that multiple factors lead to the progression of NAFLD from steatosis to NASH. The current discussion is over-focused on the role of autophagy and has not covered microbiome, an important contributor to the pathogenesis of obesity and NAFLD.5 Microbiome directly regulate the gut–liver axis. It also affects the bioactivities of metabolites, such as bile acids and short chain fatty acids. The mTOR pathway is known to interact with the microbiome.6 There are research efforts on resorting gut microbiota to prevent NAFLD via activating AMPK signaling pathway. Microbiota-derived tryptophan metabolites indole-3-acetate (I3A) and tryptamine (TA) were used to treat NAFLD in the experimental models.7 In reviewing the report from Marcondes-de-Castro et al.2 and other papers,5, 7 one wonders how gut microbes and/or metabolites may causally impact the NAFLD in the background of various lifestyles. Clinicians should be aware that these liver–gut–microbial interactions related to the disease progression and treatment responsiveness. We are expecting significant progress in the field of gut–liver–microbiome axis in the NAFLD research. Advancements in genomic analysis techniques, like genome-wide association studies (GWAS), have identified multiple genetic variants associated with an increased risk of NAFLD. Tian and Wang provided genomic insight into the pathogenesis of NAFLD.3 They specifically summarized the genes with NAFLD-associated mutations, highlighting phospholipid remodeling and spatially clustered loci as common pathological and genetic features of these mutations. Among these genes, TM6SF2 variants links to increase liver fat and a higher risk of NASH but paradoxically may reduce cardiovascular risk. PNPLA3 has been consistently associated with hepatic fat accumulation, progress to NASH, and advanced fibrosis. PNPLA3 gene encodes a lipase that plays a role in triglyceride metabolism in the liver. HSD17B13 is an interesting gene that certain genetic variations could be protective against the progression of NAFLD. As the authors indicated, a complex yet intriguing mechanism of dissociated steatosis and insulin resistance, which is observed in a subset of patients, suggesting the need for more precise therapy against NAFLD. Epigenetic modifications are also under investigation. Many studies are now conducted across different ethnic groups and geographies, leading to a broader understanding of NAFLD risk factors and prevalence. Understanding the genetic underpinnings helps in risk stratification, early diagnosis, and tailoring interventions for NAFLD patients. While published data have provided insights into NAFLD, there is a scarcity of long-term data on disease progression and outcomes. Despite the advancements, there is not a universally accepted set of criteria to define and differentiate NAFLD, NASH, and related conditions. NAFLD can range from simple steatosis to aggressive NASH, making it challenging to standardize interventions and measure outcomes across studies. Despite numerous studies, there are still limited FDA-approved therapeutic options for NASH, a more severe form of NAFLD. As the global NAFLD continues to rise, the urgency to understand and combat the disease is more pressing than ever. Current studies often utilize a combination of molecular biology, genomics, and metabolomics, providing a comprehensive understanding of NAFLD's pathogenesis. The interplay between cellular pathways like AMPK/mTOR and genomic factors paints a multifaceted picture of NAFLD's pathogenesis. Given the association between NAFLD and lifestyle factors, e.g., diet and physical activity, community-based interventions and public health campaigns targeting healthier lifestyles can be instrumental. Emerging data suggest that gut microbiota plays a significant role in NAFLD. Human studies have found a few consistent microbiome signatures discriminating healthy persons from those with NAFLD, NASH, or cirrhosis.8 Future research might focus on microbiome modulation as a therapeutic strategy.8-10 Taken together, the multidisciplinary approaches will allow a detailed understanding of these factors associated with NAFLD, which will not only lead to a deeper appreciation of the disease's complexity but will also pave the way for more precise, personalized, and effective therapeutic interventions.
DOI: 10.1111/jgh.16407
Author: Jun Sun
Institution: University of Illinois Chicago
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4388441207