Targeting Inflammation May Not Impact Hepatic Fibrosis in MASLD, Study Finds

Tamer Sallam, MD

Credit: UCLA

Although reducing hepatic inflammation has historically been considered a critical step in mitigating fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), new research suggests decreasing inflammation does not influence the extent of fibrosis.¹

The study, published in the Journal of Clinical Investigation, explored the therapeutic potential of targeting inflammation in MASLD by examining the role of lipopolysaccharide-binding protein (LBP) function in fibrosis progression, ultimately determining loss of LBP function does not impact fibrosis.¹

“Liver fibrosis is the critical feature that creates chronic liver disease and liver cancer. If we can keep fibrosis in check then we can meaningfully impact liver disease,” Tamer Sallam, MD, corresponding author of the study and vice chair and associate professor in the department of medicine at the David Geffen School of Medicine at UCLA, said in a press release.² “For decades we have believed that targeting inflammation is one of the most important ways to reduce MAFLD. But this new research indicates that inflammation, while still important, may not be the main driver of fibrosis.”

Estimated to affect as many as 25% of people worldwide, MASLD is a type of steatosis that can eventually progress to metabolic dysfunction-associated steatohepatitis (MASH). Among those with MASLD, up to 20% go on to develop MASH, which can eventually lead to cirrhosis. Targeting fibrosis before progression to cirrhosis is important for improving outcomes, and addressing hepatic inflammation has been proposed as a prerequisite to developing liver fibrosis that should be addressed with treatment. However, the role of inflammation in fibrosis progression is not well understood.³

To investigate the interplay between innate immune responses and fibrosis, investigators assessed LBP function in mouse models and studied genetic analyses from large human datasets and human tissue samples from patients with MASLD. Driven by findings suggesting mice without LBP in their liver cells had no change in fibrosis despite lower levels of liver inflammation and improved liver function, investigators then examined the consequences of LBP function loss in humans with MASLD.¹

In a cohort of patients with MASH, investigators found hepatic LBP expression strongly segregated the degree of liver inflammation, but not steatosis or fibrosis. Genome-wide association studies revealed a strong association between coding mutations in LBP and circulating markers of inflammation known to be important in MAFLD, such as serum IL-15 levels (P = 8 x 10-163). Further investigation in an independent cohort of patients with MASH confirmed a positive correlation between circulating IL15RA and LBP levels.¹

Based on these findings, investigators suggest human LBP may be protective against hepatic inflammation, but with minimal impact on fibrosis. Acknowledging hepatic scarring is a crucial driver of liver disease-related morbidity and mortality, they assert these results have significant implications for approaches aiming to target inflammation and reduce fibrosis in MASLD.¹

“Reducing scar burden is one of the holy grails in the treatment of advanced liver diseases,” Sallam said.² “These results suggest that certain ways of targeting inflammation may not be a viable option and that more directed therapies against other pathways could help us better target fibrosis and improve outcomes for patients.”

References

1. ^{Wang D, Baghoomian A, Zhang Z, et al. Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD. J Clin Invest. 2024. https://doi.org/10.1172/JCI179752}
2. ^{UCLA Health Sciences. Study finds targeting inflammation may not help reduce liver fibrosis in MAFLD. EurekAlert! July 26, 2024. Accessed July 26, 2024. https://www.eurekalert.org/news-releases/1052505}
3. ^{Cleveland Clinic. Metabolic Dysfunction-Associated Steatotic Liver Disease. Diseases & Conditions. February 5, 2022. Accessed July 26, 2024. https://my.clevelandclinic.org/health/diseases/22437-non-alcoholic-fatty-liver-disease}