Abstract

In recent years, long non-coding RNAs (lncRNAs) have emerged as critical players in regulating biological processes at various levels. LncRNAs modulate the target genes through interacting with DNA, RNA, or protein, which have been found to regulate various physiological and pathological activities. Current studies have reported lncRNAs played an important role in lipid metabolism via diverse pathways. Dysregulation of lipid metabolism is closely related to various metabolic diseases, including obesity, fatty liver disease, and cancer. To further understand the mechanisms of lncRNAs in lipid metabolism, we focus on the role of lncRNAs in fatty acid and cholesterol biosynthesis, catabolism, and transferring, aiming to exploit relevant signaling pathways.

Introduction

Advanced development in high-throughput technologies has revealed that nearly 98% of the mammalian genome was transcribed into ncRNAs (Johnsson et al., 2014), which indicates that this genomic dark matter may exert diverse functions in multiple biological processes (Gibb et al., 2011). According to the size, the ncRNA can be divided into two major classes: small non-coding RNAs (< 200 bp) and long non-coding RNAs with > 200 bp in length (Gomes et al., 2013). Like mRNAs, lncRNAs were mainly transcribed by RNA polymerase II, then capped at 5′ ends and polyadenylated at 3′ ends (Derrien et al., 2012). The structure characteristics of lncRNAs confer their functional roles. LncRNAs affect diverse aspects of cellular functions, including epigenetic modification, transcription regulation, RNA stabilization, translational modulation, and signaling transduction (Batista & Chang, 2013; Geisler & Coller, 2013). All of these aspects are vital to maintaining organism homeostasis. Recent studies have focused on the roles of lncRNAs in metabolism reprogramming in various diseases, such as cancers (Dallner et al., 2019; Sang et al., 2021; Zheng et al., 2017).

Lipid metabolism is elementary for life sustentation that balances activities between synthesis and degradation (Currie et al., 2013). Dysregulation of lipid metabolism is mainly related to diverse metabolic diseases, including obesity and diabetes (Samuel & Shulman, 2012) and hepatic carcinoma (Feng et al., 2020). To investigate how lncRNAs regulate lipid metabolism, we summarized the roles of lncRNAs in fatty acid biosynthesis and oxidation (Fig. 1), cholesterol synthesis and catabolism (Figs. 2 and 3), and lncRNAs participate in cholesterol efflux, influx, and lipoprotein formation (Fig. 3). Further exploration of the mechanisms of lncRNAs in regulating lipid metabolism reveals lncRNAs functions in nutrient sensing and maintenance of metabolic homeostasis. It will facilitate the development of novel strategies for preventing and diagnosing metabolic-related diseases.

LncRNAs regulate fatty acid biosynthesis and oxidation. Cytoplasmic acetyl-CoA is produced from ACLY-catalyzed citrate and ACSS-catalyzed acetate. Glucose contributes to citrate production from mitochondrial pyruvate oxidation in the TCA cycle. Fatty acid biosynthesis starts from the conversion of acetyl-CoA to malonyl-CoA by ACC. Acetyl-CoA and malonyl-CoA are then catalyzed into palmitic acid by FASN. LncRNA NEAT1 participates in the first conversion step via affecting ACC, and HAGLR regulates FASN in the palmitic acid generation step. Finally, palmitic acid is desaturated into unsaturated FAs by SCD. The first step of fatty acid oxidation is ACSL1, and CPT1 catalyzes fatty acid into Acyl-CoA regulated by HULC and HCP5, respectively. Classical arrows indicate activation, blunted arrows denote inhibition. LncRNAs are shown in blue

LncRNAs regulate cholesterol de novo synthesis. Bile acids are de novo synthesized by acetyl-CoA and Acetoaceyl-CoA regulating by LncRNAs. Classical arrows indicate activation, blunted arrows denote inhibition. LncRNAs are shown in blue

LncRNAs regulate cholesterol biosynthesis and lipid transferring. Cholesterol is synthesized from acetyl-CoA through a series of reactions using HMGCR and other rate-limiting enzymes. In addition to de novo biosynthesis, the cholesterol carried by LDL particles in the blood is taken up by LDLR. Surplus cholesterol is exported to the blood by ABCA1. Classical arrows indicate activation, blunted arrows denote inhibition. lncRNAs are shown in blue

Characteristics of LncRNAs

LncRNAs have been found to regulate various physiological and pathological activities by interacting with DNA, RNAs, and proteins in the nucleus or cytoplasm (Lin et al., 2017; Sang et al., 2021; Zheng et al., 2017). LncRNAs can be categorized into four groups based on their positions relative to nearby protein-coding genes: (1) Intergenic lncRNAs, named lincRNAs, are transcribed from DNA sequences between two protein-coding genes; (2) Intronic lncRNAs, produced from introns of protein-coding genes; (3) Overlapping lncRNAs are transcribed from the overlapped known protein-coding genes; and (4) Antisense lncRNAs are generated from protein-coding genes but transcribed in an opposite direction (Katayama et al., 2005; Marques & Ponting, 2014; Mattick & Rinn, 2015; Ulitsky & Bartel, 2013).

In the nucleus, lncRNAs function as enhancers, decoys, scaffolds, or guides. LncRNAs can directly interact with DNAs to regulate gene expression. In addition, lncRNAs bind specific proteins to form lncRNA–protein complexes to modify the expression of target genes cooperatively (Ding et al., 2019). In the cytoplasm, lncRNAs compete with microRNAs to bind with mRNAs to regulate the stability or translation (Zhang et al., 2014a; Zhang, 2014b).

Cellular and organism energy homeostasis and nutrient sensing are essential for survival and physiological processes. Aberrant responses are related to the occurrence of diseases. LncRNAs cooperate with diverse molecules, including metabolic enzymes and key signal regulators, to regulate the metabolisms of glucose, lipids, and amino acids (Lin, 2020; Ortiz-Pedraza et al., 2020; Singer et al., 2019). Our previous studies have revealed that lncRNA growth–arrest-specific 5 (GAS5) modulated the tricarboxylic acid cycle by disturbing the metabolic enzyme tandem association of fumarate hydratase and malate dehydrogenase and citrate synthase by acting as a tumor suppressor to maintain cellular energy homeostasis (Sang et al., 2021). Moreover, LncRNA CamK-A, a cytosolic lncRNA, was involved in the Ca2+ related signal pathways to modulate the glucose metabolism in breast cancer (Sang et al., 2018). In addition to glucose metabolism, lncRNAs are also critical regulators in lipid metabolism (Singh et al., 2018). For example, lncRNA PU.1 AS modulates triacylglycerol homeostasis by interacting with EZH2 protein to inhibit Sirtuin 6 mRNA and protein expression, thereby decreases the expression of SREBP-1c and lipid accumulation (Dong et al., 2019).

Fatty acid and cholesterol metabolism

Fatty acid metabolism

Lipids are used in energy storage and metabolism and function as signaling molecules in cellular activities (Rohrig & Schulze, 2016). The fatty acid can be esterified to form triglycerides (TG) stored in lipid droplets during high nutrient availability or hydrolyzed to generate ATP by fatty acids oxidation (also called β-oxidation) under energy stress conditions (Currie et al., 2013). Cholesterol is a substrate of the synthesis of fat-soluble vitamins and steroid hormones (Luo et al., 2020; Prabhu et al., 2016). Evidence reported that highly proliferative cells need more lipid and cholesterol provided by either uptake of exogenous dietary sourced lipids or de novo syntheses (Rysman et al., 2010). Multiple molecules, including SREBP1 (Kotzka et al., 2011), SHP (Zhang et al., 2017), and LncRNAs (Zhao et al., 2017), regulate lipid metabolism and dynamic maintenances. Besides phospholipids as the components of lipid molecules, cholesterol is also the primary precursor of the cell membrane.

Cholesterol metabolism

Cholesterol homeostasis is also essential for cellular and systemic functions and is maintained through the coordinated modulation of endogenous biosynthesis and dynamic transferring (Libby et al., 2019). Cholesterol synthesis is an energetically expensive process and starts from Acetyl-coenzyme A (acetyl-CoA). It needs continuous energy inputs from ATP, oxygen, and the reducing factors NADPH and NADH. Besides, it can be subtly regulated through a series of factors and enzymes, such as sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) (Fig. 3). Acetyl-CoA serves as a vital precursor molecule for both fatty acid and cholesterol synthesis (Luo et al., 2020). Depending on cholesterol levels, fatty acid or cholesterol synthesis is activated, resulting in cholesterol uptake or efflux.

LXR in fatty acid and cholesterol metabolism

Liver X receptors (LXRs) and SREBPs are considered the most important regulators in cholesterol and fatty acid biosynthesis processes. SREBPs is a family of helix–loop–helix leucine zipper transcription factors (Horton et al., 2003), identified with three isoforms: SREBP1a, SREBP1c, and SREBF2. SREBP1 mainly regulates the expression of fatty acid biosynthesis genes, while SREBP2 preferentially controls cholesterol synthesis gene expression. SREBP1 gene encodes SREBP1a and SREBP1c and SREBP2 gene encodes SREBP2 (Brown & Goldstein, 1997; Horton et al., 2003). Contrary to SREBPs, which are activated in response to low cellular sterol levels, LXRs are upregulated in response to high cellular sterol levels. LXRs consist of two different isoforms: LXRα and LXRβ (Hong & Tontonoz, 2014). LXRs function as sterol sensors in response to cellular sterol loading. LXR and retinoid X receptor (RXR) form heterodimers as transcription factors, which promote the expression of cholesterol efflux-related genes and SREBP1c (Sallam et al., 2016).

LncRNAs in fatty acid metabolism

Fatty acids come from either exogenous sources or de novo fatty acid syntheses. Most human cells prefer exogenous sources, yet tumor cells synthesize de novo fatty acids and frequently show a shift toward fatty acid syntheses (Medes et al., 1953; Ookhtens et al., 1984). Glucose metabolism feeds into fatty acid metabolism at the citrate point, an intermediate in the Krebs cycle. Several steps are required to convert carbons from citrate to fatty acids. A variety of enzymes are involved and regulate fatty acid homeostasis. Enzymes essential for cell growth are involved, such as ATP citrate lyase (ACLY or ACL), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN or FAS), and fatty acid-CoA ligase (ACS or ACSL) (Currie et al., 2013).

As flexible regulators, lncRNAs could function as competitive endogenous RNA (ceRNA) via directly sponging of microRNA, which further regulating the expression of genes. For example, the snoRNA host gene 16 (SNHG16) is highly up-regulated in colorectal adenomas. SNHG16 may act as a ceRNA “sponging” miRNAs to make miRNAs miss their targets. Most interestingly, half of the miRNA families targeting SNHG16 also target the 3′ UTR of the Stearoyl-CoA Desaturase (SCD) sequence. SCD participates in lipid metabolism and is downregulated upon SNHG16 silencing. Thus, SNHG16 may play an oncogenic role in the development of colorectal cancer and regulate genes involved in lipid metabolism, while exact mechanisms are unclear (Christensen et al., 2016). What's more, lncRNAs participate in various signal pathways, including the fatty acid metabolism pathway. Thus, lncRNAs affect fatty acid metabolism (as shown in Fig. 1 and Table 1) by directly or indirectly regulating enzymes.

LncRNAs and fatty acid synthesis

LncRNAs NEAT1 and uc.372 promote lipid synthesis

LncRNA nuclear enriched abundant transcript 1 (NEAT1) is an oncogenic lncRNA and notably upregulated in lung cancer and breast cancer cells (Qian et al., 2017; Sun et al., 2017). Recent studies have reported that lncRNA NEAT1 played an essential role in lipid metabolism. LncRNA NEAT1 regulates the expression of ACC and FAS mRNA and actives the mTOR/S6K1 pathway, leading to lipid accumulation. Conversely, knockdown of lncRNA NEAT1 moderates TG, cholesterol elevation and alleviates non-alcoholic fatty liver disease (NAFLD) (Wang, 2018). Sun et al. showed that lncRNA NEAT1 bound to miR-140 and acted synergistically with miR-140 to accelerate the progression of NAFLD through impairing AMPK/SREBP1 signaling transduction. Silence of miR-140 or NEAT1 alleviates NAFLD, which further confirms the role of LncRNAs NEAT1 in promoting lipid synthesis (Sun et al., 2019). Similar to NEAT1, LncRNA uc.372 also influences ACC and FAS. LncRNA uc.372 is upregulated in livers of db/db mice, HFD-fed mice, and NAFLD patients (Guo et al., 2018). LncRNA uc.372 binds to pri-miR-195/pri-miR-4668 and then inhibits the maturation of miR-195/miR-4668 to promote the expression of genes related to lipid synthesis, including ACC, FAS, stearoyl-CoA desaturase 1 (SCD1), and genes related to lipid uptake, such as CD36 (also known as FA translocase). It further promotes lipid accumulation in liver cells, resulting in NAFLD progression (Guo et al., 2018).

LncRNA HAGLR promote lipogenesis

HAGLR gene contains eight exons, and its transcript is a novel lncRNA (Zakany et al., 2017). It is transcribed from the HOXD cluster on human chromosome 2q31.2 in an antisense manner. HAGLR expression is upregulated in the majority of non-small cell lung cancer (NSCLC). In addition, knockdown of HAGLR decreases the content of cellular free fatty acid in cancer cells. Depletion of HAGLR also significantly suppressed the proliferation and invasion of non-small cell lung cancer cells. Furthermore, HAGLR overexpression partly promotes fatty acid synthase and NSCLC progression by activating FASN (Lu et al., 2017).

LncRNAs MALAT1 and H19 stabilize lipogenesis

Metastasis related to lung adenocarcinoma transcript 1 (MALAT1), an oncogenic long non-coding RNA, has been associated with liver cancer (Hou et al., 2017). In addition, a study showed that MALAT1 promoted hepatic steatosis and insulin resistance. Sterol regulatory element-binding protein SREBP-1c is expressed abundantly in hepatocytes and regulates the expression of genes required for lipogenesis (Kotzka et al., 2011). The expression of SREBP-1c and its target genes are significantly increased in the liver of NAFLD patients (Nakamuta et al., 2009). MALAT1 interacts with SREBP-1c and stabilizes its protein in hepatocytes inducing hepatic lipid accumulation (Yan et al., 2016). Similarly, lncRNA H19 stabilizes the SREBP-1c by interacting with Polypyrimidine tract-binding protein 1 (PTBP1), which regulates mRNA stability and pre-mRNA splicing. LncRNA H19 interacts with PTBP1 to facilitate the interaction with SREBP-1c mRNA and protein, leading to enhanced stability and nuclear transcriptional activity, further stimulating the lipogenic program (Liu et al., 2018).

LncRNAs Blnc1 promotes lipogenesis

Brown fat lncRNA 1 (Blnc1) has been shown to regulate the differentiation of brown and beige adipocytes as a nuclear lncRNA (Zhao et al., 2014). Zhao et al. showed that lncRNA Blnc1 was overexpressed in the livers from high-fat diet (HFD) fed mice. In response to LXR activation, overexpression of Blnc1 enhances the induction of SREBP1c, which upregulates the expression of hepatic lipogenic genes leading to lipogenesis, and eventually induces hepatic steatosis (Zhao et al., 2018).

LncRNAs lncHR1 and Gm16551 suppress lipogenesis

Contrary to MALAT1 and H19, long non-coding RNA HR1 (lncHR1) inhibits the expression of SREBP-1c at the protein level and lipid synthesis in vitro (Li et al., 2017). Mechanistically, Li et al. found that lncHR1 decreased the SREBP-1c protein level by attenuating the phosphorylation levels of key molecules in the PDK1/AKT/FoxO1 signaling pathway (Li et al., 2018). Like lncHR1, lncRNA Gm16551, identified as a metabolism-related lncRNA exclusively expressed in the liver, inhibits the SREBP-1c activities (Yang et al., 2016). In addition, liver-specific knockdown of Gm16551 upregulates ACLY, a critical enzyme in the lipogenesis process. Thus, taken together, LncRNAs lncHR1 and Gm16551 suppress lipogenesis by suppressing the SREBP-1c activities (Yang et al., 2016).

LncRNAs and fatty acid oxidation

LncRNA HULC regulates the initial step of fatty acid oxidation

Previous studies have shown that multiple lncRNAs regulated fatty acid metabolism, including the most overexpressed lncRNAs, highly up-regulated in liver cancer (HULC) (Panzitt et al., 2007). It is the first identified ncRNA to be specifically overexpressed in hepatocellular carcinoma (HCC) (Panzitt et al., 2007). HULC positively regulates the transcriptional factor peroxisome proliferator-activated receptor alpha (PPARa) by inactivating miR-9, which induces methylation of CpG islands in its promoter, since Cui et al. confirmed that miR-9 inhibited the expression of PPARa by targeting its 3′ UTR (Cui et al., 2015a, 2015b). Given that PPARa activates the initial step of cellular fatty acid oxidation, HULC can promote lipogenesis by stimulating the intracellular lipid accumulation in vitro and in vivo by activating the PPARa pathway (Cui et al., 2015a, 2015b).

LncRNA HCP5 promotes the fatty acid oxidation

Wu et al. revealed that co-culturing gastric cancer (GC) cells and mesenchymal stem cells (MSC) improved stemness and drug-resistance of GC cells. During co-culturing, lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) was induced to facilitate stemness and chemo-resistance. Mechanistically, HCP5 interacts with miR-3619-5p to upregulate PPARG coactivator 1 alpha (PPARGC1A), increasing transcription complex peroxisome proliferator-activated receptor (PPAR) coactivator‐1α (PGC1α)/CEBPB and leads to the transactivation of CPT1, which promotes the fatty acid oxidation in GC cells(Wu et al., 2020).

LncRNAs in cholesterol metabolism

Although all cells can synthesize cholesterol, about 50% of total cholesterol biosynthesis in humans occurs in the liver (Repa & Mangelsdorf, 2000). The liver is a central and major organ for cholesterol metabolism, with the uptake and secretion of lipid molecules in hepatocytes. Therefore, we focused mainly on cholesterol metabolism in the liver. Intracellular cholesterol is processed by 7-a-hydroxylase, also named cytochrome P450 family 7 subfamily A member 1 (CYP7A), to form 7-α-hydroxycholesterol (Pullinger et al., 2002). In addition, it is then converted by cytochrome p450 family 8 subfamily B member 1 (CYP8B1) to form cholic acid (Wang et al., 2005) (as shown in Figs. 2 and 3).

LncRNA and cholesterol synthesis

LncRNA LeXis prevents cholesterol biosynthesis

LXRs are members of the nuclear hormone receptor superfamily, and activation of LXRs promotes the efflux of cholesterol from the liver (Zhang et al., 2012). Liver expressed LXR-induced sequence (LeXis) is robustly induced in response to a high-fat and LeXis high-cholesterol diet or LXR agonist GW3965. LeXis interacts with RALY, a transcriptional cofactor, to prevent cholesterol biosynthesis (Sallam et al., 2016).

LncRNA lncARSR promotes cholesterol biosynthesis

Huang et al. found that the expression of lncARSR was upregulated in patients with hypercholesterolemia. Overexpression of lncARSR resulted in the elevated expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis (Goldstein & Brown, 1990). Mechanistically, lncARSR increases the expression of mature SREBP2, a primary transcription factor of HMGCR, and activates the PI3K/Akt pathway to promote cholesterol biosynthesis in liver cells eventually (Huang et al., 2018).

LncRNA lnc030 promotes cellular cholesterol synthesis

Cancer stem cells (CSCs) are considered as the roots of cancer distant metastasis and recurrence, partially due to self‐renewal and drug resistance (Peng et al., 2017). A novel lncRNA named lnc030, highly expressed in breast cancer stem cells (BCSCs) in vitro and in vivo is pivotal in maintaining BCSCs stemness and promoting tumorigenesis. lnc030 cooperates with poly (rC) binding protein 2 (PCBP2) to stabilize the mRNA expression of squalene epoxidase (SQLE), which promotes cellular cholesterol synthesis. The increased cholesterol level, in turn, activates the PI3K/Akt pathway to maintain BCSCs stemness (Qin et al., 2021).

LncRNAs and cholesterol catabolism

Lnc-HC negatively regulates cholesterol metabolism

Lnc-HC interacts with hnRNPA2B1, an RNA-binding protein, to form an RNA–protein complex in the nucleus (Humphries & Fitzgerald, 2019). The Lnc HC–hnRNPA2B1 complex further binds to the target mRNAs of CYP7A1 and ABCA1 (Lan et al., 2016). These two genes are critical regulators in the cholesterol catabolism process (Oram & Lawn, 2001). This interaction causes cholesterol accumulation in hepatocytes (Lan et al., 2016). Furthermore, Lan et al. defined that Lnc-HC did not regulate PPARγ either through lnc-HC–protein or lnc-HC–mRNA patterns. Instead, Lnc-HC negatively regulates PPARγ expression at the post-transcriptional level through the mediator miR-130b-3p and suppresses hepatocytic lipid droplet formation. Moreover, the suppression of lnc-HC induces the PPARγ expression through decreasing miR-130b-3p expression and then aggravates the TG concentration in vivo (Lan et al., 2019). Therefore, Lnc-HC functions as a negative regulator in cholesterol metabolism both in vitro and in vivo.

LncRNA MEG3 promotes cholestasis

LncRNA MEG3 (maternally expressed gene 3) is a maternally imprinted gene, and it has been found in multiple cancers (Wei & Wang, 2017; Zhang et al., 2016). Recent studies have reported that MEG3 induced the damage of bile acid homeostasis via PTBP1. LncRNA MEG3 facilitates the binding of PTBP1 to SHP (small heterodimer partner, a nuclear receptor) and disrupts SHP mRNA. SHP is a crucial inhibitor of bile acid synthesis and is critical in maintaining normal liver functions (Zhang, Shi, et al., 2014a; Zhang, 2014b). Overexpression of MEG3 RNA in mouse liver caused degradation of SHP mRNA and cholestatic liver injury accompanied by the disruption of bile acid homeostasis. On the whole, MEG3 serves as a guide RNA scaffold to recruit PTBP1 to destabilize SHP mRNA and further cause cholestasis (Zhang et al., 2017).

LncRNA LncLSTR facilitates bile acid accumulation

LncLSTR (liver-specific triglyceride regulator) is a murine lncRNA. Li et al. found that Cyp8b1 was significantly reduced in the livers of lncLSTR Knockdown mice. Mechanistic studies revealed that lncLSTR interacted with TDP-43, a transcriptional suppressor, and formed a lncLSTR/ TDP-43 complex. The interaction of TDP-43 with lncLSTR reduces its occupancy and inhibition of the Cyp8b1 promoter. Depleting lncLSTR leads to increased binding of TDP-43 to Cyp8b1 promoter, reduced Cyp8b1 gene expression, and caused a substantial accumulation of bile acid (Li et al., 2015).

LncRNAs in transferring of lipids

Cholesterol is taken up into the polarized cells (e.g., enterocytes or hepatocytes) from low-density lipoprotein (LDL) particles via LDL receptors (LDLR) (Garcia et al., 2001). However, this influx is offset by the efflux of cholesterol. Thus, only hepatocytes, adrenal cells, and gonadal cells can catabolize the cholesterol molecule, while others need to dispose of the redundant out of cells (Luo et al., 2020). ATP-binding cassette transporter A1 (ABCA1) is partially responsible for cholesterol efflux by functioning as a gatekeeper for eliminating tissue cholesterol (Fitzgerald et al., 2010; Oram & Lawn, 2001).

Lipoprotein formation is also essential in regulating lipid metabolism by binding and transporting lipids to body tissues. Apolipoprotein A1 (APOA1), a primary component in high-density lipoprotein (HDL), is synthesized in the liver and intestine (Cheung & Albers, 1982). HDLs are the densest and smallest particles with a high protein content of APOA1. ABCA1 and lipid-free APOA1 are responsible for removing cholesterol excess from cells (Luo et al., 2020). Apolipoprotein A4 (APOA4) is a major component of HDL and triglyceride-rich lipoprotein particles to control liver triglyceride secretion (Qin et al., 2016). APOA4 is primarily synthesized in the small intestine and packaged into chylomicrons. It has different physiological functions, including lipid absorption, platelet thrombosis, and food intake (Qu et al., 2019).

LncRNAs and transporters

LncRNA MeXis facilitates cholesterol efflux

Sallam et al. noted that the gene encoding the critical cholesterol efflux mediator ABCA1 was highly induced by LXR in macrophages, other than in other cell types. They further identified the lncRNA MeXis (macrophage-expressed LXR-induced sequence) as an amplifier of the LXR-dependent transcription of the gene ABCA1. Mice without the MeXis gene showed that reduced ABCA1 expression in a tissue-selective manner. Mechanistic studies revealed that MeXis was interacted with DDX17, an established nuclear receptor coactivator (Auboeuf et al., 2002), to facilitate the coactivation of DDX17 and then enhance ABCA1 expression and cholesterol efflux (Sallam et al., 2018).

LncRNA BM450697 and RP1-13D10.2 regulate cholesterol influx in an opposite way

LncRNA BM450697 and RP1-13D10.2 have been identified as regulators of LDLR. BM450697 can downregulate the LDLR transcription level by blocking the binding of RNA polymerase II and SREBP1a on the LDLR promoter region (Ray et al., 2019). However, the mechanism of lncRNA RP1-13D10.2 activating the transcription of LDLR remains unclear, needing further exploration (Mitchel et al., 2016).

LncRNAs and lipoprotein formation

LncRNA APOA1-AS negatively regulates lipoprotein formation

LncRNA APOA1-AS negatively regulates the expression of apolipoproteins contributing to the formation or function of plasma lipoproteins. APOA1-AS is an antisense transcript of the APOA1 encoding gene, a negative transcriptional regulator of APOA1 both in vivo and in vitro. APOA1-AS modulates histone methylation by recruiting various chromatin-modifying complexes to the APOA1 gene cluster and then decreases the APOA1 expression (Halley et al., 2014).

LncRNA APOA4-AS promotes lipoprotein formation

Similar to APOA1-AS, APOA4-AS also belongs to the class of natural antisense transcripts. However, APOA4-AS is found to be a concordant regulator of APOA4 expression (Qin et al., 2016). The expression of APOA4-AS and APOA4 is significantly induced in the livers of the ob/ob mice and patients with fatty liver disease. Mechanistically, APOA4-AS interacts with an RNA-stabilising protein named human antigen R (HuR) and helps promote the stability of both APOA4-AS and APOA4 mRNA, leading to increased levels of plasma triglyceride and total cholesterol (Qin et al., 2016).

Conclusions and future perspectives

Some lncRNAs have been reported to regulate cancers, metabolic diseases (e.g., obesity, NAFLD, and atherosclerosis) by affecting lipid metabolism. These findings highlighted lncRNAs as the functional molecules. From a pharmaceutical perspective, lncRNAs are desirable targets. They can be targeted using small-molecule compounds that interact with the tertiary structure of the lncRNA, or using antisense oligonucleotides that pair with the lncRNAs sequence itself.

This review has summarized more findings, showing that lncRNAs play an essential role in lipid metabolism. However, more related researches are in need. For example, the sequences of lncRNAs are rarely conserved between humans and other species, so that it led to a question of whether these sequence-conserved lncRNAs had similar functions among different species. Moreover, the precise molecular mechanisms of lncRNAs regulating lipid metabolism under different pathological conditions remain fuzzy. In sum, this review provides a better understanding of lncRNAs in regulating lipid metabolism, pointing out lncRNAs as novel therapeutic strategies and targets for preventing and treating these diseases.

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Funding

This research was funded by National Key R& D Program of China, Grant no [2021YFC2700903], National Natural Science Foundation of China, Grant nos [81672791, 81872300], Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars, Grant no [LR18C060002].

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Authors and Affiliations

1. MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China

   Kai Lei, Lei Qu, Fangzhou Liu & Aifu Lin

2. Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, 314400, China

   Ninghui Hao, Jincheng Chen & Jian Liu

3. Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310002, China

   Ninghui Hao, Jincheng Chen & Jian Liu

4. International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China

   Aifu Lin

5. Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China

   Aifu Lin

6. Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China

   Aifu Lin

7. Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang, 310058, China

   Aifu Lin

Corresponding authors

Correspondence to Jian Liu or Aifu Lin.

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Lei, K., Qu, L., Liu, F. et al. Long non-coding RNAs regulate fatty acid and cholesterol metabolism. GENOME INSTAB. DIS. 3, 70–82 (2022). https://doi.org/10.1007/s42764-022-00070-5

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• Received29 December 2021

• Revised21 February 2022

• Accepted01 March 2022

• Published17 March 2022

• Issue DateApril 2022

• DOIhttps://doi.org/10.1007/s42764-022-00070-5

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Keywords

• lncRNA

• Lipids

• Cholesterol metabolism

• Fatty acid metabolism