RESEARCH

The liver is responsible for various tasks aimed at maintaining homeostasis:

• Macronutrient metabolism.

• Generating lipid and carbohydrate reservoirs following feeding.

• Production of alternative fuels during fasting.

• Combating systemic infections by secretion of acute phase reactants.

• Regulating systemic iron homeostasis

• Xenobiotic metabolism (e.g. drug detoxification).

Many of these functions are regulated by dynamic hepatic gene expression patterns.

Fasting

Most mammalians encounter frequent and prolonged bouts of fasting and intricate mechanisms evolved to maintain homeostasis during fasting. The liver plays a central role in the response to fasting by producing fuels to supply the energetic needs of the body. Hepatocytes produce glucose and ketone bodies that are secreted to circulation to supply extra-hepatic tissues during fasting. Our lab investigates how chromatin and transcription factors regulate the fasting response and, in particular, hepatic fuel production.

The Figure below depicts the transcription factors involved in transcriptional regulation of the hepatic fasting response (adopted from Goldstein and Hager, 2015, Trends Endocrinol Metab).

Ketogenic Diet

Ketogenic diets are nutritional regimens in which carbohydrate intake is drastically reduced and most nutrients are acquired from protein and lipids. Ketogenic diets have significant therapeutic effects in certain pathologies and is becoming increasingly popular as a lifestyle intervention for healthy individuals. 

While ketogenic diet has significant health benefits, the molecular mechanisms promoting them are unclear. We study the effect of ketogenic diet on liver chromatin and transcriptional modules and investigate their contribution to the health benefits of ketogenic diets.

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Iron Homeostasis

Iron is an essential mineral to various physiological processes (oxygen transport, host defense etc.). Plasma iron levels are tightly regulated by secreted hepatic proteins. Both iron overload and iron deficiency have detrimental outcomes. Iron overload can lead to cirrhosis, diabetes and hepatocellular carcinoma. Iron deficiency may cause immune dysfunction and neurocognitive damage. Evidence show that iron levels are regulated by altering hepatic gene transcription. However, the scope of transcriptional regulation on iron homeostasis and its importance are largely unknown. We adopt an unbiased approach to explore hepatic gene and chromatin regulation as mediators of iron homeostasis maintenance.

Transcription Factor Cooperation

The liver is constantly bombarded by endocrine, cytokine, metabolite and neuronal signals; many of which affect gene expression. Still, the healthy liver is able to produce a coherent response to these signals and maintain homeostasis.  Cooperation between TFs at the chromatin template is an efficient way to integrate and converge different signals and to produce a relevant context-dependent outcome. There are various mechanisms of TF cooperation (see Figure below) and such cooperation is a prevalent mechanism to integrate extracellular and intrinsic signals in liver cells. We study mechanisms of TF cooperation in regulating hepatic functions.