Emerging role of Insig-1 in lipid metabolism and lipid disorders

doi:10.1016/j.cca.2020.05.042

Clinica Chimica Acta

Volume 508, September 2020, Pages 206-212

https://doi.org/10.1016/j.cca.2020.05.042 Get rights and content

Highlights

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What is Insig-1.
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Insig-1 in lipid metabolism.
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Mechanisms of Insig-1 in lipid metabolism.
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Insig-1 in lipid disorders.

Abstract

Growing evidence has demonstrated that Insig-1 is intricately involved in lipid metabolism regulation and the progression of lipid disorders. Our review summarizes updated information on the role and underlying mechanisms of Insig-1 in lipid metabolism dyshomeostasis and lipid disorders. As a member of the insulin-induced gene family, insulin-induced gene 1 (Insig-1) is a six-span transmembrane protein embedded in the endoplasmic reticulum (ER) membrane. Insig-1 is widely involved in the maintenance of intracellular lipid metabolism homeostasis by controlling the activation of sterol regulatory element-binding proteins (SREBPs) and the degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Growing experimental and clinical data have identified that Insig-1 reduces lipid accumulation in hepatocytes to relieve the development of nonalcoholic fatty liver disease (NAFLD), downregulates the plasma level of free cholesterol and protects β cells against lipotoxicity to alleviate diabetic dyslipidemia. In addition, Insig-1 suppresses adipogenesis and inhibits the differentiation of preadipocytes to prevent the occurrence of obesity. Insig-1 is a key regulatory factor that maintains intracellular lipid metabolism homeostasis and is a promising therapeutic target for lipid disorders.

Introduction

Lipid metabolism homeostasis is fundamental for maintaining the normal physiological function of organisms and is precisely maintained by various lipid-related genes, including those encoding for sterol regulatory element-binding proteins (SREBPs) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). SREBPs promote de novo synthesis and uptake of cholesterol and fatty acids, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) accelerates the synthesis of cholesterol [1], [2]. In addition, the low-density lipoprotein receptor (LDLR) and the group B type I scavenger receptor (SR-BI) mediate the uptake of extracellular cholesterol into cells [3], [4]. The ATP-binding cassette transporter superfamily facilitates cholesterol efflux from the intracellular compartment [5]. These proteins encoded by lipid-related genes possess diverse functions that cooperatively maintain lipid metabolism homeostasis. When these lipid-related genes are abnormally expressed or their functions become aberrant, lipid metabolism becomes imbalanced, causing lipid disorders such as nonalcoholic fatty liver disease (NAFLD), diabetic dyslipidemia and obesity [6], [7], [8]. Therefore, the upstream regulatory mechanism needs to be explored to ensure that these lipid-related genes function correctly in lipid metabolism processes.

Insulin-induced gene 1 (Insig-1), a newly discovered regulator of lipid metabolism, has recently attracted substantial attention. The Insig-1 protein encoded by Insig-1 was initially identified in a gene expression profile analysis of regenerating liver and insulin-treated Reuber H35 cells [9]. With the greater understanding of Insig-1 gained in recent decades, researchers have discovered that it is extensively involved in the regulation of intracellular lipid metabolism and that the abnormal expression of Insig-1 is widely involved in various lipid disorders. Numerous studies have demonstrated that the expression of Insig-1 is usually lower than normal in some lipid disorders characterized by an imbalance in lipid metabolism, while overexpression of Insig-1 significantly relieves the disorder in lipid metabolism and reduces the risk of lipid disorders [10], [11], [12]. Additional studies discovered that Insig-1 maintains the homeostasis of intracellular lipid metabolism by regulating SREBPs and HMGR, thereby inhibiting the development of lipid disorders [13], [14], [15].

However, the role and regulatory mechanisms of Insig-1 in lipid metabolism processes remain unclear. We summarize the current knowledge of Insig-1 in the regulation of lipid metabolism and the progression of lipid disorders. First, we describe the discovery and structural characterization of Insig-1, and then we expound on the effect of Insig-1 on lipid metabolism and the underlying molecular mechanisms. Finally, we discuss the involvement of Insig-1 in the development of lipid disorders, which advances our understanding of its role in the imbalance in lipid metabolism and the future implications for the treatment of lipid disorders.

Section snippets

The identification of Insig-1

As a key metabolic organ, the liver expresses multiple lipid genes involved in various aspects of lipid metabolism. In 1993, through a gene expression profile analysis, Insig-1 was first identified in regenerating liver and insulin-treated Reuber H35 cells [9]. Subsequently, Li et al. discovered that the expression of Insig-1 was dramatically elevated in the adipose tissue of Sprague-Dawley rats at the onset of diet-induced obesity [11]. However, the function of Insig-1 was unclear until Yang’s

Evidence from in vitro studies showing that Insig-1 modulates lipid levels

Numerous cytological analyses have demonstrated a direct association between Insig-1 and lipid metabolism. Originally, Yang et al. demonstrated that overexpression of Insig-1 inhibits the activation of SREBPs, the key transcription factor of cholesterol synthesis, thereby downregulating intracellular cholesterol levels in 293S cells transfected with Insig-1 cDNA [14]. On the basis of this study, increasing evidence has confirmed that Insig-1 has a significant effect on lipid metabolism. In

Insig-1 regulates lipid metabolism by inhibiting SREBPs activation

Insig-1 regulates the activation of SREBPs to maintain intracellular lipid metabolism homeostasis by controlling the transfer of the SCAP-SREBP complex from the ER to the Golgi apparatus (Fig. 2). SREBPs are important transcription factors involved in the regulation of cholesterol and fatty acid levels in mammals [30]. The SREBP proteins located in the ER are inactive until transferred to the Golgi apparatus by the SCAP escort and then converted through proteolytic processing into active

Insig-1 and NAFLD

Insig-1 alleviates hepatic cholesterol and fatty acids accumulation and relieves the pathological progress of nonalcoholic fatty liver disease (NAFLD) by regulating the activation of SREBPs and/or the degradation of HMGR (Table 2). NAFLD represents a spectrum of diseases ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis, which are characterized by excessive lipid accumulation in hepatocytes [26]. The pathogenesis of NAFLD is often attributed to

Conclusions, limitations and prospects

Insig-1 is a key regulator of lipid metabolism and a promising therapeutic target to combat lipid disorders. The third and fourth transmembrane helices of Insig-1 bind with hydroxysterol/SCAP to control the activation of SREBPs and the degradation of HMGR, maintaining the homeostasis of intracellular lipid metabolism. Insig-1 inhibits the synthesis and uptake of cholesterol and fatty acids to reduce the accumulation of lipids in hepatocytes, relieving the development of NAFLD. Moreover, Insig-1

Declaration of Competing Interest

The authors have no conflicts of interest to declare.

Acknowledgments

The authors gratefully acknowledge the financial supports from the National Natural Sciences Foundation of China (Grant Number: 81770460), China, Third Level of Chuanshan Talent Project of the University of South China (Grant Number: 2017CST20), China, Aid Program from the Science and Technology Bureau of Hengyang City, (Grant Number: 2017KJ268), China, and Key Lab for Clinical Anatomy & Reproductive Medicine from the Science and Technology Bureau of Hengyang City, (Grant Number: 2017KJ182),

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¹: These authors contributed equally to this work.

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ReviewEmerging role of Insig-1 in lipid metabolism and lipid disorders

Highlights

Abstract

Introduction

Section snippets

The identification of Insig-1

Evidence from in vitro studies showing that Insig-1 modulates lipid levels

Insig-1 regulates lipid metabolism by inhibiting SREBPs activation

Insig-1 and NAFLD

Conclusions, limitations and prospects

Declaration of Competing Interest

Acknowledgments

Cell. Metab.

Fish. Shellfish. Immu.

J. Lipid. Res.

J. Biol. Chem.

Mol. Cell.

Cell

Cell. Metab.

Genomic

Trop. Anim. Health. Pro.

J. Biol. Chem.

Peptides.

J. Biol. Chem.

J. Dairy. Sci.

J. Dairy. Sci.

Reprod. Toxicol.

J. Biol. Chem.

J. Lipid. Res.

Biochimie.

Cell. Metab.

J. Lipid. Res.

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP

Nat. Cell. Biol.

Low-density lipoprotein receptor (LdLr) family orchestrates cholesterol homeostasis

J. Biol. Med.

Invited review: Architectures and mechanisms of ATP binding cassette proteins

Biopolymers

Review
Emerging role of Insig-1 in lipid metabolism and lipid disorders