TABLE 2.
Annotations of the 23 key genes associated with lipid and cholesterol metabolism, glucose homeostasis and inflammation.
| Group | Gene symbol | Gene ID | Log2FC (pre/post-group) | Annotations | References |
| Colon_2W | Kcnn1 | ENSMUSG00000002908 | 1.02 | Insulin secretion, potassium ion transport | Encodes potassium voltage-gated channel and some medicines promote GLP-1 secretion via inhibition of its expression (Shin et al., 2012, 2014). |
| Adcy6 | ENSMUSG00000022994 | 1.42 | Insulin secretion, inflammatory mediator regulation of TRP channels, regulation of lipolysis in adipocytes | Involved in GLP-1 mediated signaling pathway (Dillon et al., 2005; Doyle and Egan, 2007). | |
| Hdac1 | ENSMUSG00000028800 | 1.23 | Positive regulation of interleukin-1 production, positive regulation of tumor necrosis factor production, negative regulation of insulin secretion | Promote B cell proliferation (Yamaguchi et al., 2010) and IFN mediated innate immunity (Xu et al., 2009). | |
| Lgals9 | ENSMUSG00000001123 | 1.21 | Positive regulation of interleukin-1 production, positive regulation of tumor necrosis factor production, response to lipopolysaccharide, positive regulation of defense response to bacterium, positive regulation of innate immune response, positive regulation of macrophage activation, positive regulation of T cell migration | Encode galectin-9 which could induce T helper cells to secrete pro-inflammatory cytokine IFNγ and TNFα (Su et al., 2011) and synergized with LPS to activate transcriptional factor NF-IL6, then transactivated inflammatory cytokine genes IL1A, IL1B, and IFNγ (Matsuura et al., 2009). | |
| Colon_4W | Cmya5 | ENSMUSG00000047419 | 1.01 | Negative regulation of calcineurin-NFAT signaling cascade | Inhibit the activity of NFAT (Kielbasa et al., 2011) which are key regulators of T cell development and function (Macian, 2005). |
| Atp2b4 | ENSMUSG00000026463 | 1.07 | Negative regulation of calcineurin-NFAT signaling cascade | Inhibit the activity of NFAT (Buch et al., 2005). | |
| Liver_2W | Pon1 | ENSMUSG00000002588 | –1.36 | Cholesterol metabolic process, aromatic compound catabolic process, response to fatty acid | Associated with HDL level and important in lipid and cholesterol metabolism and cardiovascular health (Macharia et al., 2012). |
| Dhcr24 | ENSMUSG00000034926 | –1.29 | Cholesterol metabolic process, lipid metabolic process, cholesterol biosynthetic process | Encode enzyme catalyzing the first step of cholesterol biosynthesis (Waterham et al., 2001). | |
| Hmgcs1 | ENSMUSG00000093930 | –1.19 | Cholesterol metabolic process, lipid metabolic process, cholesterol biosynthetic process | Encode enzyme catalyzing the last step of cholesterol biosynthesis (Mathews et al., 2014). | |
| Hnf1a | ENSMUSG00000029556 | –1.28 | Cholesterol metabolic process, reverse cholesterol transport, fatty acid biosynthetic process, fatty acid transport, regulation of insulin secretion, glucose homeostasis, maturity onset diabetes of the young | Encode HNF-1α which activates the transcription of apoM, a major component of HDL particles (Richter et al., 2003), and it can affect plasma levels of HDL, reverse cholesterol transport and cholesterol metabolism (Babaya et al., 2003). Hnf1a–/– mice had abnormal HDL particles and suffered from hypercholesterolemia (Shih et al., 2001). Besides, HNF-1α can transactivate insulin I gene (Emens et al., 1992) and it had been reported that Hnf1a knockout mice developed non-insulin-dependent diabetes mellitus (Lee et al., 1998). | |
| Cyp7a1 | ENSMUSG00000028240 | 1.43 | Cholesterol metabolic process, cholesterol homeostasis, cholesterol catabolic process, lipid metabolic process, PPAR signaling pathway, cellular response to glucose stimulus | Encode the rate-limiting enzyme in the conversion of cholesterol to bile acids and plays an important role in bile acid biosynthesis and cholesterol homeostasis (Russell and Setchell, 1992; Pullinger et al., 2002). | |
| Ppara | ENSMUSG00000022383 | –1.22 | Regulation of lipid transport by positive regulation of transcription from RNA polymerase II promoter, lipid metabolic process, Adipocytokine signaling pathway, positive regulation of fatty acid oxidation, negative regulation of cholesterol storage, PPAR signaling pathway, non-alcoholic fatty liver disease, glucose metabolic process, response to insulin, positive regulation of gluconeogenesis, regulation of glycolytic process by positive regulation of transcription from RNA polymerase II promoter, insulin resistance, negative regulation of inflammatory response, negative regulation of leukocyte cell–cell adhesion | Play a major regulatory function in lipid catabolism, activation of which can induce fatty acid oxidation, enhance lipolysis and increase energy utilization (Reddy and Hashimoto, 2001; Guzmán et al., 2004). In addition, activation of it can inhibit inflammation and many preclinical experiments demonstrated benefits of PPARα agonists in various inflammation-associated diseases (Gervois and Mansouri, 2012). Moreover, activation of it can lead to improvement of insulin sensitivity (Haluzik and Haluzik, 2006). | |
| Hnrnpk | ENSMUSG00000021546 | –1.20 | Regulation of lipid transport by positive regulation of transcription from RNA polymerase II promoter, regulation of low-density lipoprotein particle clearance, cellular response to insulin stimulus | Encode hnRNP K protein, a transactivator of LDLR gene which mediates plasma LDL clearance (Li and Liu, 2010). | |
| Acsl1 | ENSMUSG00000018796 | –1.14 | Adipocytokine signaling pathway, lipid metabolic process, lipid biosynthetic process, fatty acid metabolic process, fatty acid transport, triglyceride metabolic process, PPAR signaling pathway | Activate fatty acids (Ellis et al., 2010a) and directed fatty acid toward β-oxidation (Ellis et al., 2010b). Acsl1 specific knockout could significantly decrease fatty acid oxidation rates (Li et al., 2009; Ellis et al., 2010b). | |
| Akt1 | ENSMUSG00000001729 | 1.02 | Adipocytokine signaling pathway, regulation of lipolysis in adipocytes, negative regulation of fatty acid beta-oxidation, positive regulation of lipid biosynthetic process, non-alcoholic fatty liver disease, glucose metabolic process, glucose homeostasis, insulin resistance, inflammatory response, T cell receptor signaling pathway, B cell receptor signaling pathway, TNF signaling pathway, AMPK signaling pathway | Involved in the development of acute inflammation (Di Lorenzo et al., 2009). Overexpressing a constitutively active Akt1 in transgenic mice and isolated neonatal cardiac myocytes decreased AMPK activity, resulting in suppressed fatty acid oxidation and glucose uptake and glycolysis (Kovacic et al., 2003). Akt1 was suspected to decrease insulin sensitivity, since improved glucose tolerance and insulin sensitivity was observed in Akt1–/– mice (Buzzi et al., 2010). | |
| Lepr | ENSMUSG00000057722 | 2.17 | Adipocytokine signaling pathway, cholesterol metabolic process, non-alcoholic fatty liver disease, leptin-mediated signaling pathway, response to leptin, positive regulation of insulin secretion involved in cellular response to glucose stimulus, glucose homeostasis, cytokine–cytokine receptor interaction, T cell differentiation, regulation of energy homeostasis, AMPK signaling pathway | Leptin enhanced immune response via acting on its receptor which is encoded by Lepr (Zarkesh-Esfahani et al., 2001) and mice deficient in Lepr are resistant to inflammation (Siegmund et al., 2004). Besides, leptin can interact with its receptor LEPR, inhibiting the expression of genes involved in lipogenesis and fatty acid synthesis and increasing the expression of genes mediating fatty acid oxidation, and stimulating fatty acid oxidation by activating AMPK (Liang and Tall, 2001; Minokoshi et al., 2002). | |
| Socs3 | ENSMUSG00000053113 | 4.18 | Adipocytokine signaling pathway, non-alcoholic fatty liver disease, negative regulation of insulin receptor signaling pathway, type II diabetes mellitus, insulin resistance, negative regulation of inflammatory response, TNF signaling pathway | Promote inflammation (Liu et al., 2008; Liu et al., 2015). Negative regulator of leptin receptor signaling, can inhibit fatty acid oxidation and mediate leptin resistance and diet-induced obesity (Bjorbak et al., 2000; Steinberg et al., 2006). Can impair insulin sensitivity via degradation of IRS1 and IRS2 or inhibition of receptor tyrosine phosphorylation (Rui et al., 2002; Senn et al., 2003). Socs3 tissue specific deficiency enhanced insulin sensitivity and protected against obesity- associated insulin resistance (Sachithanandan et al., 2010; Jorgensen et al., 2013). | |
| Pnpla2 | ENSMUSG00000025509 | –1.02 | Regulation of lipolysis in adipocytes, lipid metabolic process, lipid catabolic process, triglyceride catabolic process, lipid storage, lipid homeostasis | Encode ATGL which catalyzes the first step of triglyceride hydrolysis (Zimmermann et al., 2004). In Pnpla2–/– mice, fatty acid release was reduced and massive triglyceride was accumulated (Haemmerle et al., 2006). | |
| Lmbrd1 | ENSMUSG00000073725 | 1.49 | Negative regulation of glucose import, negative regulation of insulin receptor signaling pathway, insulin receptor internalization | Encodes the LMBD1 protein that mediates endocytosis of the insulin receptor. A single-allele knockout of Lmbrd1 resulted in an enhancement of insulin receptor signaling pathway and increased glucose uptake (Tseng et al., 2013). | |
| Grb10 | ENSMUSG00000020176 | 1.58 | Negative regulation of glucose import, negative regulation of insulin receptor signaling pathway, negative regulation of glycogen biosynthetic process | Interacts with insulin receptor and is a negative regulator of insulin signaling and action (Wick et al., 2003). Loss of Grb10 in mice resulted in enhanced insulin signaling and increased insulin sensitivity (Wang et al., 2007), while overexpression of it caused postnatal insulin resistance (Shiura et al., 2005). | |
| Serpina3n | ENSMUSG00000021091 | 1.06 | Response to cytokine, acute-phase response | Encode serine protease inhibitor SERPINA3, which inhibits inflammation-associated serine proteases, such as cathepsin G, granzyme B and elastase, to prevent tissue damage during inflammatory responses (Gettins, 2002; Hsu et al., 2014). | |
| Osmr | ENSMUSG00000022146 | 1.16 | Response to cytokine, cytokine–cytokine receptor interaction | Encode OSM receptor, through which OSM can increase the expression of diverse pro-inflammatory molecules, including IL-6, gp130, and IL1-R1 (Le Goff et al., 2014; West et al., 2017). | |
| Timp4 | ENSMUSG00000030317 | 1.42 | Response to cytokine, response to lipopolysaccharide | Encode matrix metalloproteinases (MMPs) inhibitor, which plays anti-inflammatory function by inhibiting MMPs activity and decreasing TNF-α and IL-1 expression (Celiker et al., 2002). |