Biology subjects

Temel, R. E.

Publications and source records attributed to Temel, R. E..

5 recordsLinked to original sources

bioRxiv2026

A positively selected microRNA controls a reversible aging program in striated muscle

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

molecular biology↗

bioRxiv2025

ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet

The ABCG5 ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols, but is also the primary mediator of biliary cholesterol secretion in the cholesterol elimination pathway. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols remain constant, indicating the presence of a G5G8-independent mechanism for cholesterol excretion. Transintestinal cholesterol elimination (TICE) is thought to compensate for biliary G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of G5G8. Differences were not observed in fecal neutral sterols between control, acute, and chronic liver-specific G5G8 deficient mice (G5G8LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporting enzymes in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol free and cholesterol enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate fecal neutral sterol excretion, G5G8LKO and G5G8-/- mice fail to do so and accumulate sterol in the liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8-deficiency in response to dietary cholesterol in mice.

physiology↗

bioRxiv2023

Regional Heterogeneity of Aortic Histology and Transcriptomes in Young Cynomolgus Monkeys

BackgroundThe regional heterogeneity of vascular components and transcriptomes is an important determinant of aortic biology. This notion has been explored in multiple mouse studies. In the present study, we examined the regional heterogeneity of aortas in non-human primates. MethodsAortic samples were harvested from the ascending, descending, suprarenal, and infrarenal regions of young control monkeys and adult monkeys provided with high fructose for 3 years. The regional heterogeneity of aortic structure and transcriptomes was examined by histological and bulk RNA sequencing analyses. ResultsImmunostaining of CD31 and SMA revealed that endothelial and smooth muscle cells were distributed homogeneously across the aortic regions. In contrast, elastic fibers were less abundant and dispersed in the infrarenal aorta compared to other regions and associated with collagen deposition. Bulk RNA sequencing identified a distinct transcriptome related to the Notch signaling pathway in the infrarenal aorta with significantly increased NOTCH3 mRNA compared to other regions. Immunostaining revealed that NOTCH3 protein was increased in the media of the infrarenal aorta. The abundance of medial NOTCH3 was positively correlated with the dispersion of elastic fibers. Adult cynomolgus monkeys provided with high fructose displayed vascular wall remodeling, such as smooth muscle cell loss and elastic fiber disruption, predominantly in the infrarenal region. The correlation between NOTCH3 and elastic fiber dispersion was enhanced in these monkeys. ConclusionsAortas of young cynomolgus monkeys display regional heterogeneity of their transcriptome and the structure of elastin and collagens. Elastic fibers in the infrarenal aorta are dispersed along with upregulation of medial NOTCH3. HIGHLIGHTS- The present study determined the regional heterogeneity of aortas from cynomolgus monkeys. - Aortas of young cynomolgus monkeys displayed region-specific aortic structure and transcriptomes. - Elastic fibers were dispersed in the infrarenal aorta along with increased NOTCH3 abundance in the media. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/530901v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@164c52corg.highwire.dtl.DTLVardef@ccfda8org.highwire.dtl.DTLVardef@213064org.highwire.dtl.DTLVardef@f007c3_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2021

Renal Angiotensinogen in Nonhuman Primates is Predominantly Liver-Derived

AGT (Angiotensinogen) is the unique substrate of the renin-angiotensin system. Liver is the primary source of circulating AGT. The present study determined whether hepatocyte-derived AGT regulates renal AGT accumulation by injecting ASO (antisense oligonucleotides) targeting hepatocyte-derived AGT (GalNAc AGT ASO) into female cynomolgus monkeys. Hepatocyte-specific inhibition of AGT led to profound reductions of plasma AGT concentrations. AGT protein in S1 and S2 of renal proximal tubules was greatly diminished by GalNAc AGT ASO. Given the similarity between nonhuman primates and human, our findings support the notion that renal AGT is predominantly derived from liver, and liver regulates renal angiotensin II production in humans. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/444555v2_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@292f5aorg.highwire.dtl.DTLVardef@1e3e0aborg.highwire.dtl.DTLVardef@1b331e3org.highwire.dtl.DTLVardef@1904dba_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2020

The Prorenin Receptor and its Soluble Form Contribute to Lipid Homeostasis

Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter driven Cre to delete specifically PRR in hepatocytes (Liver PRR KO mice). Hepatic PRR deletion did not change the body weight but increased liver weights. Liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic LDLR protein than control mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic SREBP2 and HMG CoA-R genes. In addition, hepatic PRR deletion increased plasma sPRR levels. In vitro studies in Hep-G2 cells demonstrated that sPRR treatment up-regulated SREBP2 suggesting that elevated plasma sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PPAR{gamma}, PRR and total sPRR were elevated in the adipose tissue of Liver PRR KO mice suggesting that elevated plasma sPRR originated from the adipose tissue. In 3T3-L1 cells, sPRR treatment up-regulated PPAR{gamma} indicating that sPRR stimulates master regulator of adipocyte differentiation. Overall, this work support a new role for sPRR in lipid metabolism and adipose tissue - liver crosstalk.

physiology↗