Editorial for “In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1‐13C]Pyruvate in a Guinea Pig Model of Life‐Long Western Diet Consumption and Non‐Alcoholic Fatty Liver Disease Development”

Abstract

Editorial for “In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-C] Pyruvate in a Guinea Pig Model of Life-Long Western Diet Consumption and Non-Alcoholic Fatty Liver Disease Development” Nonalcoholic fatty liver disease (NAFLD) covers a histological spectrum, ranging from excess fat deposits to hepatic inflammation and to eventual scarring or cirrhosis. NAFLD is considered the most prevalent liver disease and remains without any approved therapy. The ongoing search for pharmacological treatment necessitates an understanding of the metabolic pathways and corresponding therapeutic targets. The rising importance of metabolic dysregulation has even led to clarifying nomenclature and use of the term metabolic dysfunction-associated fatty liver disease. Given the heterogeneity of the disease, subphenotyping will be required to indicate the predominant pathophysiological pathways, and imaging can play a key role in identifying these. In clinical trials, magnetic resonance imaging-proton density fat fraction (MRI-PDFF) remains the foremost imaging modality to assess and monitor liver steatosis, and magnetic resonance (MR) elastography is gaining traction for measuring liver stiffnesses as a surrogate for fibrosis. Yet, to understand the various metabolic pathways, more sophisticated methods are required. NAFLD is known to be tightly correlated with suppression of glucose production resulting from increased gluconeogenesis and decreased hepatic glycogen synthesis. A number of pharmacologic therapies in development focus on targeting different aspects of these pathways. In this issue, Smith et al applied MR spectroscopy (MRS) of hyperpolarized C pyruvate in a “lean NAFLD” guinea pig model to monitor enzyme activity. Developed in the early 2000s, hyperpolarized C MRS provides increased signaling with improved peak-to-peak resolution and is a useful tool for monitoring cellular metabolism on a short time scale. Pyruvate is a commonly studied compound in liver metabolism as it plays a critical role in lipid synthesis and glucose homeostasis in the fed and fasting states. Previous work that modeled NAFLD in rats using a high fat diet given for 6 weeks showed alanine and lactate were significantly increased over control diet. In the current study, the researchers used the Western diet-induced steatotic guinea pig model. Western diet feeding is commonly used in rodents to induce multiple aspects of NAFLD, including hepatic triglyceride accumulation and weight gain. In the current study, chronic Western diet feeding in guinea pigs resulted in increased liver steatosis but did not result in weight gain, consistent with other Western diet steatotic guinea pig models and the lean NAFLD phenotype. In the current model, MRS showed a decrease in lactate time-to-peak indicating an increase rate of lactate production and shift from oxidative metabolism to anaerobic glycolysis. This study also included MRI-PDFF assessments of hind limb, visceral and subcutaneous adipose tissue, as well as whole body. The Western diet animals showed lower body volume, but elevated liver volume along with a reduction in adipose tissue. It is anticipated that to track therapeutic effects and provide a noninvasive alternative to liver biopsy, a multiparametric imaging approach is necessary for monitoring both liver and overall body composition changes associated with comorbid phenotypes. In summary, Smith et al, have demonstrated imaging tools for understanding the etiology of NAFLD and the enzymatic reaction-based metabolic pathways that address the corresponding pathogenic factors. Though initial C MRS studies in nonobese NAFLD subjects had shown conflicting results, hyperpolarized MRS techniques have potential for clinical applications and facilitating identification of novel therapeutic targets. The anticipated use of MRS in early phase trials to monitor response to intervention at the