A Research Blog

Touted as the most common cause of liver failure worldwide, non-alcoholic steatohepatitis (NASH) manifests as inflammation and increased lipotoxicity in liver cells. Accumulation of fat in the liver has been cited as the cause of NASH. Specifically, the accumulation of saturated fatty acids, such as palmitic acid, in liver cells triggers inflammation, and results in oxidative stress and tissue damage. However, not everyone with fat accumulation in the liver develops NASH. Why is that?

Group photo

Pictured, from left to right: Dr. Jin Zhou, Prof Paul Yen and Asst Prof Rohit Sinha

Professor Paul Yen, Assistant Professor Rohit Sinha, Dr. Jin Zhou and their team from the Cardiovascular and Metabolic Disorders Programme at Duke-NUS Medical School are working hard at dissecting the genetic signature of NASH. With current treatment options for NASH limited, and mainly focusing on the control of common risk factors such as obesity and type 2 diabetes, the hope is that a better understanding of the genetics behind NASH will uncover gene targets that may be leveraged to develop novel therapeutics.

Here, we take a look at two recent studies published by the team that further delves into the genes involved in NASH and their role in lipotoxicity.

Fat Mass and Obesity Associated (FTO) Gene

In genome-wide association studies, FTO gene expression was found to be correlated with obesity and type 2 diabetes. This study published in Biochemical and Biophysical Research Communications investigates FTO gene expression in NASH. In both humans and mice, FTO gene expression is elevated with NASH. The silencing of FTO appears to protect liver cells against palmitate-induced oxidative stress, thereby reducing lipotoxicity and, possibly, the effects of NASH. These findings highlight the possibility of using FTO inhibitors to reduce lipotoxicity in NASH.

Unc-51 Like Kinase (ULK1) GeneULK1

The second study, published in Autophagy, looks at the role of ULK1 in NASH and identified an additional role for ULK1, beyond mediating starvation-induced general autophagy. ULK1 appears to protect liver cells against lipotoxicity and oxidative stress by regulating the expression of stearoyl-Coenzyme A desaturase 1 (SCD1). SCD1 is known to convert saturated fatty acids into mono-unsaturated fatty acids, which are then stored in lipid droplets within the cell and removed from the cell’s internal environment where is may cause damage.

ULK1 was found to augments SCD1 expression, thereby ensuring sufficient SCD1 is produced to prevent toxic saturated fatty acids from exerting its harmful effects within liver cells. Hence, it can be inferred that the loss of ULK1 results in a reduction of SCD1 expression and offers liver cells reduced protection from saturated fatty acids and ensuing lipotoxicity and oxidative stress. Consequently, NASH livers show a reduced expression of ULK1, which may contribute to the onset of lipotoxicity and tissue damage observed. Findings from this study identify ULK1 as a possible gene target for the development of novel therapeutics to treat NASH.

Funding Information
The work for both publications was supported by the National Research Foundation, Singapore, under its Clinician Scientist Award (NMRC/CSA/0054/2013) and Clinician Scientist Independent Research Grant (NMRC/CIRG/1340/2012) administered by the Singapore Ministry of Health’s National Medical Research Council, and by Singapore Ministry of Health’s National Medical Research Council (NMRC/BNIG/2025/2014)


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