Fatty Liver Disease
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now the most common chronic liver condition worldwide. Closely linked to obesity, insulin resistance, and type 2 diabetes, MASLD encompasses a spectrum of disorders ranging from simple hepatic steatosis to steatohepatitis (MASH), fibrosis, cirrhosis, and even hepatocellular carcinoma. Despite its growing prevalence and serious long-term consequences, no approved pharmacological treatments currently exist to effectively halt or reverse MASLD progression.
Liver-directed therapies that address both the root metabolic causes and the inflammatory progression of MASLD are urgently needed. A key challenge lies in understanding the molecular drivers that initiate and sustain hepatic fat accumulation, inflammation, and fibrogenesis under conditions of metabolic stress.
The Role of the Endocannabinoid System
The endocannabinoid/CB1R system plays a pivotal role in regulating hepatic lipid metabolism. CB1R activation in the liver promotes de novo lipogenesis, reduces fatty acid β-oxidation, and contributes to insulin resistance, all hallmarks of MASLD pathogenesis. Peripheral CB1 receptor signaling also modulates adipose tissue lipolysis, further increasing free fatty acid flux to the liver.
Our research has demonstrated that pharmacological blockade of peripheral CB1Rs not only prevents steatosis but can also reverse established liver damage in obese mouse models, offering a promising therapeutic strategy devoid of central nervous system side effects.
Our Approach
Our lab adopts a comprehensive and mechanistic strategy to decipher how peripheral CB1R signaling contributes to the onset and progression of fatty liver disease. We aim to uncover how CB1R modulates hepatic lipid accumulation, mitochondrial dysfunction, cellular stress responses, and hepatocyte-immune interactions, all of which are critical components of MASLD pathogenesis.
To address these questions, we employ a multidisciplinary platform that integrates:
-
Genetically engineered mouse models, including hepatocyte-specific and liver-specific CB1R knockout mice, to define tissue-specific contributions of CB1R signaling in vivo.
-
Pharmacological interventions using peripherally restricted CB1R antagonists, allowing us to isolate peripheral effects without central nervous system involvement.
-
Multi-omics profiling, including hepatic metabolomics, lipidomics, and transcriptomics, to map CB1R-driven metabolic reprogramming.
-
Advanced in vitro systems, such as 3D human liver spheroids, to model human hepatic steatosis and evaluate drug effects in a physiologically relevant context.
-
Lipotoxicity assays and live-cell imaging to monitor lipid droplet accumulation, mitochondrial respiration, and oxidative stress in primary hepatocytes and liver-derived cell lines.
-
Discovery and functional validation of additional non-cannabinoid targets that act in parallel or downstream of CB1R in liver metabolic dysfunction.
This integrated approach allows us not only to evaluate therapeutic efficacy but also to gain mechanistic insights into how CB1R blockade restores metabolic homeostasis. Our goal is to identify key molecular checkpoints in hepatic lipid metabolism and inflammation that can be leveraged for next-generation therapies targeting MASLD and MASH.
Related Publications
Attenuating the rate of total body fat accumulation and alleviating liver damage by oral administration of vitamin D-enriched edible mushrooms in a diet-induced obesity murine model is mediated by an anti-inflammatory paradigm shift
Drori A, Rotnemer-Golinkin D, Avni S, Drori A, Danay O, Levanon D, Tam J, Zolotarev L, Ilan Y
Attenuating the rate of total body fat accumulation and alleviating liver damage by oral administration of vitamin D-enriched edible mushrooms in a diet-induced obesity murine model is mediated by an anti-inflammatory paradigm shift
Drori A, Rotnemer-Golinkin D, Avni S, Drori A, Danay O, Levanon D, Tam J, Zolotarev L, Ilan Y
Attenuating the rate of total body fat accumulation and alleviating liver damage by oral administration of vitamin D-enriched edible mushrooms in a diet-induced obesity murine model is mediated by an anti-inflammatory paradigm shift
Drori A, Rotnemer-Golinkin D, Avni S, Drori A, Danay O, Levanon D, Tam J, Zolotarev L, Ilan Y
