UCLA

Liver is a key regulator of systemic metabolism in physiology and pathology. It maintains cholesterol, triglyceride and glucose homeostasis in response to fasting and feeding. Transcription factors responsive to hormones and nutrients coordinate many of these responses. They regulate gene networks relating to lipid, glucose and amino acid metabolism during fasting and feeding, and factors such as sex, circadian rhythms and dietary content interact with these transcriptional programs, as reviewed in chapter 1. Understanding the different players in these processes and how they interact with each other will be key to develop strategies to combat metabolic diseases. Recent advances in probing the transcriptional landscape, coupled with high throughput sequencing approaches such as assay for transposase accessible chromatin (ATAC-Seq), have enabled the identification of transcriptional regulators of these processes and their interrelationships. In chapter 2, I describe results from a screen using ATAC-Seq and RNA-Seq to profile novel transcriptional regulators of the hepatic response to fasting and feeding. We determined GATA4 expression and activity to be upregulated by feeding through insulin. Knocking out Gata4 in adult liver impaired the transcriptional and metabolic response to feeding. Additionally, loss of hepatic GATA4 led to a reduction in HDL cholesterol and to the accumulation of liver triglycerides. These effects were accompanied by the downregulation of genes involved in cholesterol efflux and triglyceride hydrolysis, and the upregulation of genes involved in lipid uptake. Furthermore, hepatic GATA4 colocalized and collaborated with Liver X Receptor (LXR), a key regulator of cholesterol transport. In chapter 3, I investigated the dynamics of hepatic LXRs via ATAC-Seq and RNA-Seq in wild-type and LXRα/β knockout liver. Loss of LXRs in liver changed the transcriptional regulatory landscape by reducing accessibility at enhancers and increasing accessibility at promoters. A broad set of transcription factors that bind enhancers, including nuclear receptors, had reduced activity based on their motif accessibility, showing their reliance on LXRs. Moreover, this investigation demonstrated that LXR also functions as a transcriptional repressor of certain genes. Overall, these studies revealed important functions for GATA4 and LXR within hepatic transcriptional networks, extending our understanding of transcriptional regulation of hepatic lipid metabolism.