Steatotic liver disease is steadily increasing in prevalence worldwide. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD, formerly named Non-Alcoholic Fatty Liver Disease), specifically, is underdiagnosed clinically and is characterized by steatosis, the accumulation of lipids in the liver. 

Presently, no FDA-approved medication exists to target steatotic liver disease. Rather, dietary interventions and drastic weight loss are currently the mainstay for treating disease progression. Further, genes implicated in liver metabolism, such as those in lipid and glycogen homeostasis, have not been completely characterized. It is therefore critical to understand the role that diet plays on liver metabolism and subsequent systemic manifestations. The Ketogenic Diet (KD), a low-carbohydrate and high-fat diet, has previously been established as an effective treatment in several neurologic and gastrointestinal conditions. KD also has been shown to reduce lipid accumulation, improve weight loss, lipid profiles, and glycemic traits in patients with MASLD or Metabolic Syndrome, yet it is not sufficiently understood how it does so.

MASLD has known polygenic underpinnings. In particular, Protein Phosphatase 1 Regulatory Subunit 3B (PPP1R3B) (chromosome 8q23.1), is a gene with known associations to MASLD, Cardiovascular Disease, and Type II Diabetes. PPP1R3B encodes a structural protein that facilitates hepatic glycogen and lipid metabolizing enzymes. Known PPP1R3B genetic variants have been linked to traits including steatosis and markers for liver damage, quantity and quality of plasma lipids, and fasting glucose, insulin, and lactate levels. Previous studies in mice have also demonstrated that either overexpression or deletion of Ppp1R3B leads to some variation of liver disease. 

As emerging evidence suggests that KD, via gene-nutrient interactions, may regulate disease presentation and energy expenditure, we studied this hypothesis through both an in-vitro and in-vivo Ppp1R3B model. The goal of this study is to characterize the interactions between KD and genes involved in ketogenesis, lipid metabolism, and glucose-glycogen homeostasis in the liver, ultimately as potential indicators of clinical dietary effects. We were especially interested in evaluating metabolic profiles among Ppp1R3B knockout (KO) versus Wild-Type (WT) treatments, which may shed light on the role of KD as a therapeutic for hepatic and cardiometabolic diseases.