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Circadian Regulation of Apolipoproteins in the Brain: Implications in Lipid Metabolism and Disease

Lee, Chaeeun Hannah; Murrell, Charlotte Ellzabeth; Chu, Alexander; Pan, Xiaoyue
The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm disruption is an important risk factor for many diseases including neurodegenerative illnesses. The central and peripheral oscillators' circadian clock network controls the circadian rhythm in mammals. The clock genes govern the central clock in the suprachiasmatic nucleus (SCN) of the brain. One function of the circadian clock is regulating lipid metabolism. However, investigations of the circadian regulation of lipid metabolism-associated apolipoprotein genes in the brain are lacking. This review summarizes the rhythmic expression of clock genes and lipid metabolism-associated apolipoprotein genes within the SCN in Mus musculus. Nine of the twenty apolipoprotein genes identified from searching the published database (SCNseq and CircaDB) are highly expressed in the SCN. Most apolipoprotein genes (ApoE, ApoC1, apoA1, ApoH, ApoM, and Cln) show rhythmic expression in the brain in mice and thus might be regulated by the master clock. Therefore, this review summarizes studies on lipid-associated apolipoprotein genes in the SCN and other brain locations, to understand how apolipoproteins associated with perturbed cerebral lipid metabolism cause multiple brain diseases and disorders. This review describes recent advancements in research, explores current questions, and identifies directions for future research.
PMID: 38139244
ISSN: 1422-0067
CID: 5612012

Bmal1 regulates production of larger lipoproteins by modulating cAMP-responsive element-binding protein H and apolipoprotein AIV

Pan, Xiaoyue; Hussain, M Mahmood
High plasma lipid/lipoprotein levels are risk factors for various metabolic diseases. We previously showed that circadian rhythms regulate plasma lipids, and deregulation of these rhythms cause hyperlipidemia and atherosclerosis in mice. Here, we show that global and liver-specific Bmal1-deficient mice maintained on a chow or a Western diet developed hyperlipidemia, denoted by the presence of higher amounts of triglyceride- and ApoAIV-rich larger chylomicron and very-low-density lipoprotein, due to overproduction. Bmal1 deficiency decreased Shp and increased MTP, a key protein that facilitates primordial lipoprotein assembly and secretion. Moreover, we show that Bmal1 regulates Crebh to modulate ApoAIV expression and the assembly of larger lipoproteins. This is supported by the observation that Crebh- and ApoAIV-deficient mice, along with Bmal1-deficient mice with knockdown of Crebh, had smaller lipoproteins. Further, overexpression of Bmal1 in Crebh-deficient mice had no effect on ApoAIV expression and lipoprotein size. These studies ind15icate that regulation of ApoAIV and assembly of larger lipoproteins by Bmal1 requires Crebh. Mechanistic studies showed that Bmal1 regulates Crebh expression by two mechanisms. First, Bmal1 interacts with the Crebh promoter to control circadian regulation. Second, Bmal1 increases Rev-erbα expression, and Rev-erbα interacts with the Crebh promoter to repress expression. In short, Bmal1 modulates both the synthesis of primordial lipoproteins and their subsequent expansion into larger lipoproteins by regulating two different proteins, MTP and ApoAIV, via two different transcription factors, Shp and Crebh. It is likely that disruptions in circadian mechanisms contribute to hyperlipidemia, and avoiding disruptions in circadian rhythms may limit/prevent hyperlipidemia and atherosclerosis.
PMID: 34626126
ISSN: 1527-3350
CID: 5035252

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

Pan, Xiaoyue
The kidneys are organs that require energy from the metabolism of fatty acids and glucose; several studies have shown that the kidneys are metabolically active tissues with an estimated energy requirement similar to that of the heart. The kidneys may regulate the normal and pathological function of circulating lipids in the body, and their glomerular filtration barrier prevents large molecules or large lipoprotein particles from being filtered into pre-urine. Given the permeable nature of the kidneys, renal lipid metabolism plays an important role in affecting the rest of the body and the kidneys. Lipid metabolism in the kidneys is important because of the exchange of free fatty acids and apolipoproteins from the peripheral circulation. Apolipoproteins have important roles in the transport and metabolism of lipids within the glomeruli and renal tubules. Indeed, evidence indicates that apolipoproteins have multiple functions in regulating lipid import, transport, synthesis, storage, oxidation and export, and they are important for normal physiological function. Apolipoproteins are also risk factors for several renal diseases; for example, apolipoprotein L polymorphisms induce kidney diseases. Furthermore, renal apolipoprotein gene expression is substantially regulated under various physiological and disease conditions. This review is aimed at describing recent clinical and basic studies on the major roles and functions of apolipoproteins in the kidneys.
PMID: 35629966
ISSN: 2218-1989
CID: 5284072

Cholesterol Metabolism in Chronic Kidney Disease: Physiology, Pathologic Mechanisms, and Treatment

Pan, Xiaoyue
High plasma levels of lipids and/or lipoproteins are risk factors for atherosclerosis, nonalcoholic fatty liver disease (NAFLD), obesity, and diabetes. These four conditions have also been identified as risk factors leading to the development of chronic kidney disease (CKD). Although many pathways that generate high plasma levels of these factors have been identified, most clinical and physiologic dysfunction results from aberrant assembly and secretion of lipoproteins. The results of several published studies suggest that elevated levels of low-density lipoprotein (LDL)-cholesterol are a risk factor for atherosclerosis, myocardial infarction, coronary artery calcification associated with type 2 diabetes, and NAFLD. Cholesterol metabolism has also been identified as an important pathway contributing to the development of CKD; clinical treatments designed to alter various steps of the cholesterol synthesis and metabolism pathway are currently under study. Cholesterol synthesis and catabolism contribute to a multistep process with pathways that are regulated at the cellular level in renal tissue. Cholesterol metabolism may also be regulated by the balance between the influx and efflux of cholesterol molecules that are capable of crossing the membrane of renal proximal tubular epithelial cells and podocytes. Cellular accumulation of cholesterol can result in lipotoxicity and ultimately kidney dysfunction and failure. Thus, further research focused on cholesterol metabolism pathways will be necessary to improve our understanding of the impact of cholesterol restriction, which is currently a primary intervention recommended for patients with dyslipidemia.
PMID: 35503178
ISSN: 0065-2598
CID: 5216032

Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

Fang, Tingyu; Wang, Hua; Pan, Xiaoyue; Little, Peter J; Xu, Suowen; Weng, Jianping
The prevalence of non-alcoholic fatty liver disease (NAFLD) increases year by year, and as a consequence, NAFLD has become one of the most prevalent liver diseases worldwide. Unfortunately, no pharmacotherapies for NAFLD have been approved by the United States Food and Drug Administration despite promising pre-clinical benefits; this situation highlights the urgent need to explore new therapeutic targets for NAFLD and for the discovery of effective therapeutic drugs. The mouse is one of the most commonly used models to study human disease and develop novel pharmacotherapies due to its small size, low-cost and ease in genetic engineering. Different mouse models are used to simulate various stages of NAFLD induced by dietary and/or genetic intervention. In this review, we summarize the newly described patho-mechanisms of NAFLD and review the preclinical mouse models of NAFLD (based on the method of induction) and appraises the use of these models in anti-NAFLD drug discovery. This article will provide a useful resource for researchers to select the appropriate model for research based on the research question being addressed.
PMID: 36263163
ISSN: 1449-2288
CID: 5352472

Nonalcoholic fatty liver disease in CLOCK mutant mice

Pan, Xiaoyue; Queiroz, Joyce; Hussain, M Mahmood
Nonalcoholic fatty liver disease (NAFLD) is becoming a major health issue as obesity increases around the world. We studied the effect of a circadian locomotor output cycles kaput (CLOCK) mutant (ClkΔ19/Δ19) protein on hepatic lipid metabolism in C57BL/6 Clkwt/wt and apolipoprotein E-deficient (Apoe-/-) mice. Both ClkΔ19/Δ19 and ClkΔ19/Δ19 Apoe-/- mice developed a full spectrum of liver diseases (steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma) recognized in human NAFLD when challenged with a Western diet, lipopolysaccharide, or CoCl2. We identified induction of CD36 and hypoxia-inducible factor 1α (HIF1α) proteins as contributing factors for NAFLD. Mechanistic studies showed that WT CLOCK protein interacted with the E-box enhancer elements in the promoters of the proline hydroxylase domain (PHD) proteins to increase expression. In ClkΔ19/Δ19 mice, PHD levels were low, and HIF1α protein levels were increased. When its levels were high, HIF1α interacted with the Cd36 promoter to augment expression and enhance fatty acid uptake. Thus, these studies establish a regulatory link among circadian rhythms, hypoxia response, fatty acid uptake, and NAFLD. The mouse models described here may be useful for further mechanistic studies in the progression of liver diseases and in the discovery of drugs for the treatment of these disorders.
PMID: 32396530
ISSN: 1558-8238
CID: 5035222

Circadian Clock, Time-Restricted Feeding and Reproduction

Pan, Xiaoyue; Taylor, Meredith J; Cohen, Emma; Hanna, Nazeeh; Mota, Samantha
The goal of this review was to seek a better understanding of the function and differential expression of circadian clock genes during the reproductive process. Through a discussion of how the circadian clock is involved in these steps, the identification of new clinical targets for sleep disorder-related diseases, such as reproductive failure, will be elucidated. Here, we focus on recent research findings regarding circadian clock regulation within the reproductive system, shedding new light on circadian rhythm-related problems in women. Discussions on the roles that circadian clock plays in these reproductive processes will help identify new clinical targets for such sleep disorder-related diseases.
PMID: 32012883
ISSN: 1422-0067
CID: 4324902

Circadian Clock Regulation on Lipid Metabolism and Metabolic Diseases

Pan, Xiaoyue; Mota, Samantha; Zhang, Boyang
The basic helix-loop-helix-PAS transcription factor (CLOCK, Circadian locomotor output cycles protein kaput) was discovered in 1994 as a circadian clock. Soon after its discovery, the circadian clock, Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL, also call BMAL1), was shown to regulate adiposity and body weight by controlling on the brain hypothalamic suprachiasmatic nucleus (SCN). Farther, circadian clock genes were determined to exert several of lipid metabolic and diabetes effects, overall indicating that CLOCK and BMAL1 act as a central master circadian clock. A master circadian clock acts through the neurons and hormones, with expression in the intestine, liver, kidney, lung, heart, SCN of brain, and other various cell types of the organization. Among circadian clock genes, numerous metabolic syndromes are the most important in the regulation of food intake (via regulation of circadian clock genes or clock-controlled genes in peripheral tissue), which lead to a variation in plasma phospholipids and tissue phospholipids. Circadian clock genes affect the regulation of transporters and proteins included in the regulation of phospholipid metabolism. These genes have recently received increasing recognition because a pharmacological target of circadian clock genes may be of therapeutic worth to make better resistance against insulin, diabetes, obesity, metabolism syndrome, atherosclerosis, and brain diseases. In this book chapter, we focus on the regulation of circadian clock and summarize its phospholipid effect as well as discuss the chemical, physiology, and molecular value of circadian clock pathway regulation for the treatment of plasma lipids and atherosclerosis.
PMID: 32705594
ISSN: 0065-2598
CID: 5035242

BMAL1 controls glucose uptake through paired-homeodomain transcription factor 4 in differentiated Caco-2 cells

Sussman, Whitney; Stevenson, Matthew; Mowdawalla, Cyrus; Mota, Samantha; Ragolia, Louis; Pan, Xiaoyue
The transcription factor aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) is an essential regulator of the circadian clock, which controls the 24-h cycle of physiological processes such as nutrient absorption. To examine the role of BMAL1 in small intestinal glucose absorption, we used differentiated human colon adenocarcinoma cells (Caco-2 cells). Here, we show that BMAL1 regulates glucose uptake in differentiated Caco-2 cells and that this process is dependent on the glucose transporter sodium-glucose cotransporter 1 (SGLT1). Mechanistic studies show that BMAL1 regulates glucose uptake by controlling the transcription of SGLT1 involving paired-homeodomain transcription factor 4 (PAX4), a transcriptional repressor. This is supported by the observation that clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated endonuclease Cas9 (Cas9) knockdown of PAX4 increases SGLT1 and glucose uptake. Chromatin immunoprecipitation (ChIP) and ChIP-quantitative PCR assays show that the knockdown or overexpression of BMAL1 decreases or increases the binding of PAX4 to the hepatocyte nuclear factor 1-α binding site of the SGLT1 promoter, respectively. These findings identify BMAL1 as a critical mediator of small intestine carbohydrate absorption and SGLT1.
PMID: 31216190
ISSN: 1522-1563
CID: 4954852

Long noncoding RNA TUG1 promotes cell proliferation and migration of renal cell carcinoma via regulation of YAP

Liu, Shan; Yang, Yantong; Wang, Weiwei; Pan, Xiaoyue
OBJECTIVES:Recently, long noncoding RNAs (lncRNAs) have captured much attention for their important roles in human diseases. Deregulation of lncRNA taurine-upregulated gene 1 (TUG1) has been reported to regulate cancer progression in many cancer types. However, how TUG1 contributes to renal cell carcinoma (RCC) remains elusive; we were eager to resolve the questions. METHODS:Tumor tissues and the matched adjacent normal tissues were collected from patients with RCC. Messenger RNA (mRNA) levels of TUG1, yes-associated protein (YAP), and microRNA (miR)-9 levels were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The regulation of YAP by TUG1 was investigated using Western blot analysis, RT-qPCR, and immunofluorescence. The oncogenic roles of TUG1 and YAP were studied using a cell proliferation assay and a wound healing assay. The interaction of TUG1-miR-9-YAP was analyzed in RCC cell lines. RESULTS:In the current study, we observed a positive correlation between TUG1 expression and YAP expression in RCC using the Gene Expression Omnibus database and tumor tissues collected from 58 patients with RCC. The TUG1 elevation enhanced YAP expression but did not alter the Hippo-signaling pathway activity or YAP protein distribution in cells. In addition, we found that TUG1 could bind to miR-9; therefore, TUG1 could positively control YAP expression via downregulation of miR-9 level. Furthermore, we observed that inhibition of cell proliferation and cell migration induced by TUG1 silencing could be reversed by overexpression of YAP in RCC cell lines. CONCLUSIONS:Our findings indicated a pivotal role of TUG1 in driving RCC progression via regulation of miR-9/YAP, suggesting a potential therapeutic targeting role of TUG1 in RCC.
PMID: 30132963
ISSN: 1097-4644
CID: 5035192