Biology subjects

de Assis, L. V.

Publications and source records attributed to de Assis, L. V..

5 recordsLinked to original sources

bioRxiv2024

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a markedly modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THR(B) manipulation in fatty liver diseases.

physiology↗

bioRxiv2023

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. These genes participate in many known TH-associated processes. We further explored these genes and created a unique expression panel that can assess liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH state under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state in one-time point studies.

physiology↗

bioRxiv2023

Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice

Background & AimsThe liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as non-alcoholic steatohepatitis (NASH) affects daily transcriptome rhythms in the liver remains elusive. To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. Along this, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses. Approach & ResultsComparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice revealed an almost 3h phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies revealed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared to methods without time control. ConclusionsNASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEGs detection and enhances reproducibility.

physiology↗

bioRxiv2022

Grape-seed proanthocyanidin extract (GSPE) modulates diurnal oscillations of key hepatic metabolic genes and metabolites alleviating hepatic lipid deposition in cafeteria-fed obese rats in a time-of-day-dependent manner

Metabolic syndrome (MS) and its related diseases, including obesity and non-alcoholic fatty liver disease (NAFLD), have become a public health issue due to their increasing prevalence. Polyphenols, such as grape seed proanthocyanidin extract (GSPE), are bioactive compounds present in fruits and vegetables that show promise for MS treatment. We have previously demonstrated that the efficacy of this phenolic extract in the modulation of liver circadian clocks was affected by the time of the day at which it was ingested. Thus, we wondered if the beneficial effects of GSPE consumption in NAFLD could be mediated by diurnal modulation of hepatic lipid and glucose metabolism and whether GSPE effects on liver metabolism are impacted by the timing of administration. Results from hepatic lipid profiling, expression rhythm analysis of metabolic genes together with liver metabolomics in rats revealed that the CAF diet impaired glucose homeostasis and enhanced lipogenesis in the liver, leading to the generation of hepatosteatosis. Chronic consumption of GSPE at the onset of the active phase was able to restore the daily oscillation of liver mass and of key lipogenic and glycogenic genes, along with the reestablishment of liver metabolite rhythms, demonstrating hepatoprotective properties by decreasing triglyceride accumulation and lipid droplet formation in the liver, thus mitigating the development of CAF-induced NAFLD. Furthermore, in vitro data suggest that catechin, one of the main phenolic compounds found in the GSPE extract, may be involved in the ameliorating effects of GSPE against NAFLD.

pharmacology and toxicology↗

bioRxiv2022

Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15 % of the liver transcriptome as rhythmic in control and T3 groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

physiology↗