Senescent hepatocytes confer unexpected protection against metabolic liver disease

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Pittsburgh $100,228 on December 8, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the role of hepatocyte senescence in metabolic dysfunction-associated steatotic liver disease (MASLD).

The research develops and employs a novel in vivo mouse model enabling selective induction of senescence in hepatocytes to examine the effects of senescence on liver function and MASLD progression. Preliminary studies demonstrate that mice with senescent hepatocytes show reduced weight gain, adiposity, and liver fat accumulation when exposed to a Western diet, alongside improved glucose tolerance and hepatic insulin sensitivity while maintaining mitochondrial respiratory capacity. The research tests the hypothesis that senescent hepatocytes exhibit increased energetic burden to maintain homeostasis, potentially conferring adaptive metabolic protection against liver fat accumulation and metabolic dysfunction during metabolic stress.

Performance occurs in Pittsburgh, Pennsylvania. The period of performance runs from December 8, 2026, through April 14, 2029. The award is structured as a Project Grant.

Abstract

This proposal aims to investigate the role of hepatocyte senescence in liver function and the development of metabolic dysfunction-associated steatotic liver disease (masld), a disease which affects about 33% of the global population. Cellular senescence, a state of irreversible cell cycle arrest triggered by multiple cellular stressors such as DNA damage and telomere shortening, is increasingly recognized as a contributor to metabolic dysfunction associated with aging, particularly in the liver, where IT is implicated in mitochondrial dysfunction, steatosis, inflammation, and fibrosis. However, the precise role of senescent hepatocytes in masld remains poorly understood. Previous studies have linked senescent hepatocytes to impaired fatty acid oxidation and liver steatosis; however, these conclusions were largely based on positive associations between histological markers of senescence and stains for cellular lipids and used models with heterogeneous senescence onset. To address these limitations, we developed a novel in vivo model where we can selectively induce senescence in hepatocytes of adult mice to investigate the effects of senescence on liver function and the progression of masld. Our preliminary studies revealed that mice with senescent hepatocytes were protected from masld by the means of reduced weight gain, adiposity, and liver FAT when exposed to a western diet. Moreover, these mice showed improved glucose tolerance and hepatic insulin sensitivity while maintaining mitochondrial respiratory capacity. These findings suggest that the energetic demands of senescence may confer adaptive metabolic benefits during short-term metabolic stress. Therefore, our central hypothesis is that senescent hepatocytes exhibit an increased energetic burden to maintain homeostasis, which may provide protective effects against liver FAT accumulation and metabolic dysfunction during short-term dietary stress. To test our hypothesis, aim 1 will assess cellular metabolism and energy expenditure in senescent hepatocytes both in vivo and EX vivo using our novel transgenic mouse model. Aim 2 will explore the molecular mechanisms that connect senescent hepatocytes with metabolic adaptation. To accomplish this, we will establish an in vitro system to induce DNA damage and use cripsr/CAS9 mediated genome editing to probe the downstream mediators of adaptation. We will also validate our in vitro finding in genetically modified mice that lack DNA damaging signal transducer CHK2. Completion of the above aims will expand our understanding of the contribution of cellular senescence to metabolic health while also providing outstanding training in advanced skills in metabolic isotope tracing, metabolic phenotyping, and molecular biology, supported by strong mentorship and career development resources.