Nonalcoholic Steatohepatitis: Natural History, Pathogenesis and Therapy

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD) is marked by accumulation of fat in liver cells with accompanying inflammation and variable degrees of cell injury and fibrosis. When cell injury and fibrosis are present, the disease has a potential to progress and is referred to as steatohepatitis (MASH, previously termed NASH), which can lead to cirrhosis, liver cancer, morbidity and mortality. The etiology of MASH is not clear nor is there an approved treatment modality for it. MASLD has become an extremely common disorder, estimated to affect up to 30% of individuals in the US. Unfortunately, it commonly goes unrecognized, as demonstrated by our finding that over a 5-year period, 28% of subjects enrolled as healthy volunteers to studies at the NIH Clinical Center were likely to have underlying NAFLD. As such, there is a clear need to understand the pathophysiology of the disease and its treatment. Our focus on MASLD is three-fold: first, we aim to identify and characterize key genes that play a role in the pathogenesis of MASLD through the use of genetic studies and cell- or animal models and identify their suitability as therapeutic target. Second, we aim to understand the physiology of fat accumulation and injury in the liver, especially as it relates to handling of oral caloric load. Third, we hope to identify and refine effective treatments for the disorder. Genetic studies identified single nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting MASLD. We initiated a study to investigate whether these SNPs are associated with histological severity in a large cohort of MASLD patients. We confirmed the association of the rs738409G allele in the PNPLA3 gene with steatosis and were first to describe its association with histological severity. In pediatric patients, the high-risk rs738409G allele was associated with an earlier presentation of disease. Similarly, we discovered an association of several loss-of-function SNPs in the gene for 17-beta hydroxysteroid dehydrogenase type 13 (HSD17B13) with histological features of NAFLD. HSD17B13 is an enzyme that we found to be predominantly expressed in the liver and to colocalize with lipid droplets. We established an assay for its enzymatic activity and clarified that genetic variants that lead to loss of enzymatic function are genetically associated with protection from severity of MASLD. We further characterized the structure of the protein and the domains in it that are key to its function. These findings generated remarkable interest in the pharmaceutical industry and several HSD17B13 inactivating agents are being studied in human subjects as potential therapies for MASH. Despite the promising genetic association and pharma interest, the actual physiological role of HSD17B13 in vivo and the mechanism by which its inactivation leads to protection from MASH-associated injury are still unknown. To improve our understanding of HSD17B13s role, we established an Hsd17b13 knock-out mouse model and are currently studying it under multiple conditions, aiming to replicate the human phenotype. Our mouse and cell models allow us to pinpoint the mechanism by which loss of HSD17B13 protects the liver from injury, as well as its association with other metabolic features. As MASLD is intricately related to food intake and energy metabolism, we are undertaking clinical trials to evaluate the handling and fate of nutrients by the fatty liver. We used the BreathID real-time breath test device in combination with a labeled fatty acid to demonstrate a decrease in the rate of fatty acid oxidation in subjects with MASLD compared to controls. We recently studied MASLD subjects after ingestion of a liquid mixed meal. We collected plasma samples at multiple time points and utilized a lipidomic approach and parallel mouse models to identify an increase in packaging of hepatic diacylglycerols (DAG) into very low density lipprotein (VLDL) particles after a meal, that is unique to MASLD. Finally, we are currently performing an additional study, where liver samples from subjects with MASLD are obtained before and after an oral carbohydrate load aimed to elucidate the hepatic transcriptomic and lipidomic response as well as effects on intra-hepatic insulin signaling. In an ongoing clinical trial, subjects with MASLD are treated with semaglutide, a glucagon like peptide 1 (GLP-1) receptor agonist with effectiveness against MASH previously shown. This study aims to elucidate the mechanism of action of semaglutide in treating MASH, its effects on the liver lipidome and identify early predictors of clinical response. MASLD is commonly associated with having overweight or obesity. However, excess liver fat can also occur in lipodystrophy, a disorder in which adipose tissue is deficient. Comparing the pathways leading to liver fat accumulation in regular MASLD to the pathways in people with lipodystrophy can highlight the role of the adipose tissue and of secondary adaptation to its loss. For that purpose, we collaborate with Dr. Rebecca Brown from NIDDK on comparative studies of MASLD and lipodystrophy-associated fatty liver.