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Review
. 2020 Aug 6;10(8):1154.
doi: 10.3390/biom10081154.

Not So Slim Anymore-Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

Amir Sapir  1
Affiliations
Review

Not So Slim Anymore-Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

Amir Sapir. Biomolecules. .

Abstract

One of the basic building blocks of all life forms are lipids-biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism-the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors-and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases.

Keywords: SREBPs; SUMO; SUMO proteases; fatty acid metabolism; lipid metabolism; metabolism of cholesterol; nuclear receptors; steroid hormones.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
The Small Ubiquitin-like Modifier (SUMO) conjugation cycle: The names of the enzymes are based on mammalian nomenclature. After SUMO cleavage (not shown), SUMO is conjugated to a heterodimeric E1 ligase complex (SAE1/2). Next, SUMO is transferred to the E2 ligase (Ubc9). Finally, the SUMO-Ubc9 molecule forms a complex with an E3 ligase (e.g., PISA1–4) and with the target protein. This complex formation facilitates the transfer of SUMO to a specific lysine residue on the sequence of the target protein. Alternatively, SUMO conjugation to the E2 ligase, Ubc9, can be followed by the direct transfer of SUMO to the protein target independently of E3 ligase activity. Substrates can be conjugated with a single SUMO (monoSUMOylation), with multiple SUMO peptides on different lysine residues (multiSUMOylation), or with a chain of SUMO2/3 tags (polySUMOylation). SUMO-specific proteases (named SENtrin-specific Proteases (SENPs) in mammals and Ubiquitin-Like Proteases (ULPs) in nonmammalian organisms cleave SUMO from its protein substrate in order to reverse SUMO conjugation and activity.
Figure 2
Figure 2
Types of lipids that are suggested to be regulated by SUMOylation: Collection and classification of lipids based on textbook literature [19]. The red frames label lipids that are suggested to be regulated by SUMOylation. These include, for example, ergosterol in yeasts [24,25,26]; isoprenoids in C. elegans [27]; and, in mammals, cholesterol [28], bile acids [29,30], and free fatty acids [31,32]. Lipids are grouped by their biological functions and not by their chemical properties. Cholesterol has both structural and nonstructural roles; thus, it appears in two different categories. * Vitamin D is a byproduct of cholesterol, but it is grouped with other vitamins based on its biological function.
Figure 3
Figure 3
Two prominent cases of the regulation of SREBP-dependent lipid metabolism by SUMOylation: (A) In specific physiological conditions, the hormone Insulin-like Growth Factor 2 (IGF-2) activates two mitogen-activated protein kinases, ERK1 and ERK2, in order to phosphorylate SREBP2. This regulated phosphorylation reduces the level of SREBP2 SUMOylation, thus, leading to the upregulation of genes that encode enzymes of sterol metabolism, including the LDL receptor (LDLR), squalene synthase, and HMG-CoA synthase [28]. In the absence of the IGF-2 signal, SREBP2 SUMOylation leads to the inhibition of the transcriptional activity of SREBPs through the recruitment of a corepressor complex that includes the histone deacetylase 3 (HDAC3) [28]. (B) In fasting conditions, the secretion of the mouse fasting hormone, glucagon, from the pancreas activates Protein Kinase A (PKA), which phosphorylates SREBP1c on serine 308. This phosphorylation increases the levels of SREBP1c SUMOylation, leading to its ubiquitination-dependent degradation. SREBP1c degradation results in the inhibition of lipogenesis in order to switch the metabolic state of the organism toward catabolism [33]. This mechanism was further elucidated by the overexpression of the SUMO E3 ligase, PIAS4, in obese db/db mice, which leads to the inhibition of lipid synthesis. Moreover, the suppression of PIAS4 activity in lean mice triggers the expression of SREBP1c target genes that stimulate hepatic lipogenesis [33].
Figure 4
Figure 4
Two cases-in-point of the regulation of lipid homeostasis by the SUMOylation of nuclear receptors (NRs). (A) In a mouse model system, Liver Receptor Homolog-1 (LRH-1) coordinates programs of reverse cholesterol transport (RCT) and cholesterol metabolism. SUMOyaltion of LRH-1 results in the recruitment of the transcriptional-repressor PROspero-related homeoboX 1 (PROX1) to the LRH-SUMO protein. The LRH/PROX1 complex inhibits the expression of genes that function in RCT and in cholesterol and bile acid excretion [29]. UnSUMOylated LRH-1 also promotes SREBP1 activation and the execution of lipogenesis programs in the liver, which leads to the development of nonalcoholic fatty liver disease [66]. (B) In the mouse skeletal muscle-derived cell line, C2C12, the supplementation of saturated fatty acids activates the toll-like receptor 4 (TLR4) and its adaptor MyD88 [31]. This activation results in NFkB-mediated upregulation of the SUMO protease SENP2, which sheds SUMO from PPARβ/δ and PPARγ. This deconjugation leads to the transcriptional upregulation of fatty-acid oxidation-associated enzymes, such as carnitine palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). SENP2 upregulation was also demonstrated following the treatment of C2C12 cells with the hormone leptin that activates the STAT3 transcription factor [71]. In SENP2 knockout mice, leptin treatment does not upregulate CPT1b and ACSL1 levels as well as fatty acid β-oxidation, demonstrating the in vivo significance of the link between the SUMOylation of PPAR proteins and lipid metabolism [71].
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