UC Berkeley

Nonalcoholic Fatty Liver Disease (NAFLD) is a progressive liver disease that can lead to liver cirrhosis and hepatocellular carcinoma, eventually resulting in death. The disease is prevalent worldwide, affecting around a quarter of the population, and is associated with risk factors such as obesity and type 2 diabetes. Currently, no standard treatment exists for NAFLD, which is characterized by excessive hepatic lipid accumulation leading to ER and mitochondrial stress, impaired insulin signaling, and inflammatory response. These events form a vicious cycle and exacerbate the progression of NAFLD. Sirtuin 7 (SIRT7), an NAD+-dependent deacetylase, is a nutrient sensor that alleviates ER stress and mitochondrial protein folding stress and prevents fatty liver. The insulin/IGF-1 signaling is the first nutrient-sensing pathway reported to regulate longevity in model organisms. Inhibiting the Insulin/IGF-1 signaling extends the lifespan of mice and worms. Paradoxically, low circulating IGF-1 is linked to hepatic steatosis and severe liver fibrosis in NAFLD. It remains unclear whether the somatotroph axis, which controls the insulin/IGF-1 signaling pathway, plays a role in liver damage during the progression of NAFLD.

This dissertation aimed to explore the underlying mechanisms of NAFLD and develop a novel therapeutic strategy to combat this progressive liver disease. Chapter 1 provided a comprehensive review of the current state of nutrient-sensing pathways and oxidative stress response. We also discussed the therapeutic opportunities to prevent aging- or disease-driven tissue dysfunction by targeting the nutrient-sensing pathways. In Chapter 2, we investigated the role of the somatotroph axis in NAFLD and identified a novel regulatory pathway involving hepatic ER stress and ATF3, which suppresses the somatotroph axis in hepatocytes and leads to decreased cell proliferation and ER stress- induced cell death. Our findings in genetic and diet-induced NAFLD mouse models suggest that the suppressed somatotroph axis prevents apoptosis and inflammation but decreases hepatocyte proliferation and exacerbates fibrosis in the livers. Finally, we demonstrated that pharmacological activation of SIRT7 via NAD+ boosting reduces hepatic ER stress, rescues the suppressed somatotroph axis, and ameliorates NAFLD pathogenesis, offering a promising new therapeutic approach for treating this disease.