Role of Beta-catenin in Regulating Hepatic Lipid Metabolism in NAFLD

Over the past few decades we have seen a steep increase in the rates of obesity and its associated conditions such as diabetes and the metabolic syndrome as more countries adapt the sedentary Western lifestyle and diet high on fat, cholesterol and sugar. Nonalcoholic fatty liver disease is thought to be the hepatic representation of the metabolic syndrome and is closely associated with insulin resistance. Genetic linkage studies have implicated mutations in Wnt signaling in the pathogenesis of insulin resistance although the mechanisms responsible are unknown. beta-catenin, the final downstream mediator of canonical Wnt signaling, regulates cell differentiation and growth, in part through its regulation of lipid metabolism.;To examine the link between the Wnt/beta-catenin signaling and insulin action, we treated high fat fed male C57BL/6 mice with an antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of beta-catenin. Four weeks of beta-catenin ASO treatment decreased beta-catenin by ≈80% in the liver and 70% in white adipose tissue relative to control ASO treated mice. Both groups had similar weight and body composition and whole body energy balance, however, beta-catenin ASO improved the plasma lipid profile with a 17% decrease in plasma cholesterol, a 37% decrease in triglyceride. beta-catenin knockdown protected mice from lipid-induced liver and peripheral insulin resistance as reflected by greater suppression of hepatic glucose production (81% vs. 30%) and a 30% increase in peripheral glucose uptake during hyperinsulinemic-euglycemic clamp. This improvement in hepatic insulin sensitivity was associated with reductions in hepatic triglyceride (34% lower) and diacylglycerol content (60% lower). Gene expression analysis showed significant suppression of genes regulating hepatic lipid re-esterification, the major pathway for liver triglyceride synthesis. Previous studies in our lab have shown that diacylglycerol (DAG) accumulation is tightly linked to. insulin resistance via novel PKC-mediated impairments in insulin signaling. The decrease in hepatic DAG content was associated with a significant decrease in PKCepsilon activation in our study as well. Downstream insulin signaling was assessed by comparing the degree of Akt phosphorylation in response to insulin in both control ASO and beta-catenin ASO treated animals. There was 64% increase in insulin stimulated pAKT/AKT ratio in beta-catenin ASO treated mice compared to controls, consistent with improved hepatic insulin signaling. In contrast, hepatic ceramide content was increased. Ceramides have been implicated in other studies as key lipid metabolites promoting insulin resistance. In our study, we were clearly able to achieve significant protection from fat-induced insulin resistance despite the increase in ceramide, suggesting that it may have limited significance to the pathogenesis of insulin resistance.;To our knowledge, this is the first time that knockdown of beta-catenin with ASO in liver and WAT was used. Reducing beta-catenin expression decreases expression of enzymes involved in fatty acid esterification, reduces hepatic steatosis in fat fed mice and protects from lipid-induced insulin resistance. These studies provide evidence for a novel role of beta-catenin in liver metabolism. It may have important practical implications as a therapeutic approach to metabolic syndrome-related conditions. Currently, there is in no universally accepted therapy for NAFLD besides hard-to-implement lifestyle changes. Some metabolic treatments have been promising in trials, but with subsequent barriers to widespread use. Given the rising prevalence of obesity, diabetes and NAFLD, new and effective strategies of controlling this epidemic are urgently needed.