Researchers Identify a Gene to Guide Novel Therapeutics of Nonalcoholic Fatty Liver Diseases

Investigators have found that the gene Asah1 plays a crucial protective role in preventing the progression of nonalcoholic fatty liver diseases (NAFLD) into more severe forms of liver disease by regulating hepatic lipid homeostasis and cellular maintenance processes. The findings from the new study opens in new tab/window in The American Journal of Pathology opens in new tab/window, published by Elsevier, have the potential to inform new therapeutic strategies and improve outcomes for NAFLD patients.

The liver functions as your body's chemical processing plant, handling fats and nutrients. However, today's lifestyle of poor diet choices and lack of exercise can cause too much fat to build up in the liver, leading to a range of metabolic conditions like NAFLD. It is estimated that about 100 million individuals in the United States (about 25% of the population) and one in three individuals in the world are affected by NAFLD. About 25% of NAFLD patients progress to a more severe stage including liver inflammation (nonalcoholic steatohepatitis, NASH) and scarring (liver fibrosis), which can lead to cirrhosis or even liver cancer. Therefore, understanding how NAFLD progresses to fibrotic NASH is important for improving the outcomes of NAFLD patients.

Impaired lysosomal function (breaking down waste) leads to accumulation of excess lipids in liver cells, worsening NAFLD and contributing to its progression. By analyzing a clinical gene-profiling dataset (GSE163211) among obese patients, researchers identified Asah1 as a significant lysosomal gene that positively correlated with NAFLD stages.

Lead investigator Yang Zhang, PhD, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, says, “NAFLD has become a major global health challenge, while current treatment options for NAFLD and NASH are still limited. The lack of approved pharmacological treatments specifically for NASH with fibrosis represents a significant unmet medical need. In this study, we emphasized the significant role of Asah1 in NAFLD progression. Although previous research had established connections between the Asah1 gene and liver disease, this study is the first to demonstrate how Asah1 specifically affects lipid processing in liver cells and influences disease progression.”

Researchers identified Asah1 [encoding a protein named acid ceramidase (AC)] as an important gene that related to the severity of NAFLD. Their data showed that removing Asah1 from liver cells significantly worsened liver damage, inflammation, and fibrosis in a model of NAFLD induced by feeding mice a high-fat and high-cholesterol diet. Further analysis showed that Asah1 deficiency increased harmful lipids accumulation, disrupted lipid metabolism, triggered cellular stress, and impaired the cell's waste disposal system. These findings demonstrate that Asah1 plays a crucial protective role in preventing the progression from simple NAFLD to more severe forms of liver disease (fibrotic NASH) by regulating hepatic lipid homeostasis and cellular maintenance processes.

Dr. Zhang continues, "This provides potential therapeutic strategies for NAFLD patients by targeting Asah1 expression or AC activity. Additionally, by monitoring liver Asah1 expression or AC activity, clinical professionals may identify patients at higher risk for disease progression and thus inform targeted intervention strategies to prevent severe liver complications such as cirrhosis and liver carcinoma and eventually improve patients’ outcomes."

Co-lead investigator Rui Zuo, MMed., PhD candidate, University of Houston, College of Pharmacy, adds: “While Asah1 deficiency affected multiple aspects of lipid metabolism, it specifically impacted cholesterol levels but not triglycerides – this selectivity was unexpected given how interconnected lipid pathways typically are. In our bodies, triglycerides and cholesterol typically work as inseparable partners in metabolism. When we consume excess calories or high-fat foods, both substances tend to accumulate in our liver simultaneously. They share common pathways for processing and transport throughout the body and are also stored together in tiny droplets (named lipid droplets) within our liver cells. That's why the findings about the Asah1 gene were particularly unexpected. When this gene was disabled in liver cells, we found that cholesterol level increased while triglyceride level remained unchanged. This would be like having two items that always move together suddenly taking different paths – one accumulating while the other stays stable. This unusual pattern suggests that the Asah1 gene plays a more specialized role in managing cholesterol but not triglycerides. It broadened our traditional understanding of how triglycerides and cholesterol are regulated during the progression of NAFLD”.

Currently, treatment options for NAFLD are limited; the main approaches focus on lifestyle modifications, particularly weight loss through diet and exercise, which are difficult for patients to maintain long-term. If left untreated, NASH can progress through stages of fibrosis to cirrhosis, at which point liver transplantation becomes the only curative option. Therefore, having effective pharmacological treatments to prevent NAFLD progression would be valuable as complementary therapeutic options. Targeting Asah1 has the potential to develop treatments that not only address the symptoms but help prevent the disease from getting worse.

Co-lead investigator Mi Wang, MD, PhD, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, concludes: “As a clinical gastroenterologist, I'm genuinely excited about what our findings could mean for patients struggling with metabolic liver diseases. What makes me particularly happy is that we've identified a specific marker – the Asah1 gene – that could help us predict which patients are at higher risk for their NAFLD becoming more severe. Right now, when I see patients with early-stage fatty liver disease, it's challenging to tell them with certainty whether their condition will stay stable or worsen. With this discovery, we might be able to offer more personalized care. If we can identify which patients have lower Asah1 expression or AC activity, we can focus on more intensive interventions on those at highest risk and perhaps take a more conservative approach with others. This kind of precision medicine is where I believe the future of liver disease treatment lies.”

Notes for editors

The article is “Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice,” by Rui Zuo, Mi Wang, Yun-Ting Wang, YangPing ShenTu, Alexandra K. Moura, Ying Zhou, Kiana Roudbari, Jenny Z. Hu, Pin-Lan Li, JiuKuan Hao, Xiang Li, and Yang Zhang (https://doi.org/10.1016/j.ajpath.2024.11.003 opens in new tab/window). It appears in The American Journal of Pathology, volume 195, issue 3 (March 2025), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(24)00444-9/fulltext opens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact Yang Zhang, PhD, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, at +1 713 743 7710 or [email protected] opens in new tab/window.

The study was supported by grants from National Institutes of Health (R01HL122937 and R01HL150007).

About The American Journal of Pathology

The American Journal of Pathology opens in new tab/window, official journal of the American Society for Investigative Pathology opens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org opens in new tab/window

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