RNA-Seq Reveals Different Gene Expression in Liver-Specific Prohibitin 1 Knock-Out Mice.

Kyuwon Lee,Hyeonju Yu,Kwang Suk Ko,Seong-Ho Lee,Jihye Lee,Byungwhi Kong,Stephanie Shouse

doi:10.3389/fphys.2021.717911

Abstract

Prohibitin 1 (PHB1) is an evolutionarily conserved and ubiquitously expressed protein that stabilizes mitochondrial chaperone. Our previous studies showed that liver-specific Phb1 deficiency induced liver injuries and aggravated lipopolysaccharide (LPS)-induced innate immune responses. In this study, we performed RNA-sequencing (RNA-seq) analysis with liver tissues to investigate global gene expression among liver-specific Phb1−/−, Phb1+/−, and WT mice, focusing on the differentially expressed (DE) genes between Phb1+/− and WT. When 78 DE genes were analyzed for biological functions, using ingenuity pathway analysis (IPA) tool, lipid metabolism-related genes, including insulin receptor (Insr), sterol regulatory element-binding transcription factor 1 (Srebf1), Srebf2, and SREBP cleavage-activating protein (Scap) appeared to be downregulated in liver-specific Phb1+/− compared with WT. Diseases and biofunctions analyses conducted by IPA verified that hepatic system diseases, including liver fibrosis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death, which may be caused by hepatotoxicity, were highly associated with liver-specific Phb1 deficiency in mice. Interestingly, of liver disease-related 5 DE genes between Phb1+/− and WT, the mRNA expressions of forkhead box M1 (Foxm1) and TIMP inhibitor of metalloproteinase (Timp1) were matched with validation for RNA-seq in liver tissues and AML12 cells transfected with Phb1 siRNA. The results in this study provide additional insights into molecular mechanisms responsible for increasing susceptibility of liver injuries associated with hepatic Phb1.

Highlights

Liver disease is a comprehensive term, including diverse stages of the disorder related to liver injury, and is one of the main causes of illness and death worldwide
Several genes, including optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2), which are involved in mitochondrial fusion and fission, contributing to mitochondrial morphology, were not differentially expressed between Prohibitin 1 (Phb1)+/− and WT
We examined the hepatic transcriptome of liverspecific Phb1 deficient mice and identified biological functions and genes associated with hepatotoxicity, lipid metabolism, and metabolic disorders

Summary

Introduction

Liver disease is a comprehensive term, including diverse stages of the disorder related to liver injury, and is one of the main causes of illness and death worldwide. The risk factors include hepatitis B and C virus, alcohol, obesity, etc., the cellular regulatory mechanisms for liver disease and accountable evidence for physiological responses are yet to be explored (Smalling et al, 2013). Gene Expression of Liver-Specific Phb KO Mice specific genes and pathway changes by liver injuries through whole transcriptome analyses of a relevant animal model. The objective of the present study was to conduct global gene expression analyses of liverspecific Prohibitin 1 (Phb1) knockout (KO) mice as a liver disease model. The protein is located to inner mitochondrial membrane and nucleus, so it regulates several important cellular processes, including apoptosis, cell proliferation, and transcriptional regulation by interacting with retinoblastoma protein (Rb), p53, and E2F transcription factors (Nijtmans et al, 2000; Ramani et al, 2016)

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