Biology subjects

Rome, F. I.

Publications and source records attributed to Rome, F. I..

6 recordsLinked to original sources

bioRxiv2026

Sulfur amino acid restriction prevents S-adenosylmethionine-driven liver steatosis, hepatocellular carcinoma, and metabolic remodeling in high-fat-fed GNMT-null mice

The expression of glycine N-methyltransferase (GNMT), a critical regulator of S-adenosylmethionine (SAM) levels, is down-regulated in humans with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). In low-fat-fed mice, GNMT knockout (KO) induces liver steatosis that progresses to HCC. This is accompanied by increased SAM and a shunting of tricarboxylic acid (TCA) cycle intermediates away from gluconeogenesis to other biosynthetic pathways that support lipid accretion and tumorigenesis. The objective of this study was to test whether this metabolic remodeling persists in GNMT KO mice with diet-induced obesity and to determine if the liver pathophysiology and metabolic dysregulation are dependent on elevated SAM. To accomplish this, GNMT KO mice and wild-type (WT) littermates were fed a high-fat control or high-fat sulfur amino acid restricted (SAAR) diet to mitigate SAM accumulation. 2H/13C isotope infusions in mice quantified in vivo liver glucose and TCA cycle fluxes. Metabolomics, respirometry, and pyruvate tolerance tests were completed to more fully interpret the 2H/13C metabolic flux analyses. KO mice had impaired gluconeogenesis sourced from TCA cycle intermediates. A concurrent elevation in metabolites of pathways that use both SAM and TCA cycle intermediates indicated increased liver polyamine turnover, transsulfuration, and de novo lipogenesis. Importantly, SAAR prevented the increase in SAM, the associated metabolic dysregulation, and the appearance of liver steatosis and HCC. In conclusion, the results of these experiments suggest that the loss of GNMT in mice with diet-induced obesity rewires metabolism in a SAM-dependent manner that precipitates liver steatosis and the transition to HCC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/738958v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@42a108org.highwire.dtl.DTLVardef@5a3b55org.highwire.dtl.DTLVardef@1ed5f2corg.highwire.dtl.DTLVardef@10346cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis

Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein ([~]70-fold), serine concentration ([~]2-fold), and 13C-serine ([~]20-fold) following an intravenous infusion of [U-13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR. Graphical AbstractSchematic representation of liver glucose adaptations to SAAR O_FIG O_LINKSMALLFIG WIDTH=132 HEIGHT=200 SRC="FIGDIR/small/682938v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@dcda30org.highwire.dtl.DTLVardef@1789003org.highwire.dtl.DTLVardef@36cd4eorg.highwire.dtl.DTLVardef@1e0c640_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Ketogenesis protects against MASLD-MASH progression through fat oxidation-independent mechanisms

AbstractThe progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) involves complex alterations in both liver-autonomous and systemic metabolism that influence the livers balance of fat accretion and disposal. Here, we quantify the relative contribution of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. We found in humans with MASH, that liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. The use of loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Disruption of mitochondrial {beta}-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of hepatic ketogenesis could serve a protective role through additional mechanisms that extend beyond quantified overall rates of fat oxidation.

biochemistry↗

bioRxiv2023

Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice

Regular exercise elicits adaptations in glucose and lipid metabolism that allow the body to meet energy demands of subsequent exercise bouts more effectively and mitigate metabolic diseases including fatty liver. Energy discharged during the acute exercise bouts that comprise exercise training may be a catalyst for liver adaptations. During acute exercise, liver glycogenolysis and gluconeogenesis are accelerated to supply glucose to working muscle. Lower liver energy state imposed by gluconeogenesis and related pathways activates AMP-activated protein kinase (AMPK), which conserves ATP partly by promoting lipid oxidation. This study tested the hypothesis that AMPK is necessary for liver glucose and lipid adaptations to training. Liver-specific AMPK12 knockout (LAKO) and wild type (WT) mice completed sedentary and exercise training protocols. Liver nutrient fluxes were quantified at rest or during acute exercise following training. Liver metabolites and molecular regulators of metabolism were assessed. Training increased liver glycogen in WT mice, but not in LAKO mice. The inability to increase glycogen led to lower glycogenolysis, glucose production, and circulating glucose during acute exercise in trained LAKO mice. Deletion of AMPK12 attenuated training-induced declines in liver diacylglycerides. In particular, training lowered the concentration of unsaturated and elongated fatty acids comprising diacylglycerides in WT mice, but not in LAKO mice. Training increased liver triacylglycerides and the desaturation and elongation of fatty acids in triacylglycerides of LAKO mice. These lipid responses were independent of differences in tricarboxylic acid cycle fluxes. In conclusion, AMPK is required for liver training adaptations that are critical to glucose and lipid metabolism. NEW & NOTEWORTHYThis study shows that the energy sensor and transducer, AMP-activated protein kinase, is necessary for an exercise training-induced: i) increase in liver glycogen that is necessary for accelerated glycogenolysis during exercise, ii) decrease in liver glycerolipids independent of TCA cycle flux, and iii) decline in the desaturation and elongation of fatty acids comprising liver diacylglycerides. The mechanisms defined in these studies have implications for use of regular exercise or AMPK-activators in patients with fatty liver.

physiology↗

bioRxiv2023

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and -ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

developmental biology↗

bioRxiv2022

Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice

Acute exercise increases liver gluconeogenesis to supply glucose to working muscle. Concurrently, elevated liver lipid breakdown fuels the high energetic cost of gluconeogenesis. This functional coupling between liver gluconeogenesis and lipid oxidation has been proposed to underlie the ability of regular exercise to enhance liver mitochondrial oxidative metabolism and decrease liver steatosis in individuals with non-alcoholic fatty liver disease. Herein we tested whether repeated bouts of increased hepatic gluconeogenesis are necessary for exercise training to lower liver lipids. Experiments used diet-induced obese mice lacking hepatic phosphoenolpyruvate carboxykinase 1 (KO) to inhibit gluconeogenesis and wild type (WT) littermates. 2H/13C metabolic flux analysis quantified glucose and mitochondrial oxidative fluxes in untrained mice at rest and during acute exercise. Circulating and tissue metabolite levels were determined during sedentary conditions, acute exercise, and refeeding post-exercise. Mice also underwent six weeks of treadmill running protocols to define hepatic and extrahepatic adaptations to exercise training. Untrained KO mice were unable to maintain euglycemia during acute exercise resulting from an inability to increase gluconeogenesis. Liver triacylglycerides were elevated following acute exercise and circulating {beta}-hydroxybutyrate was higher during post-exercise refeeding in untrained KO mice. In contrast, exercise training prevented liver triacylglyceride accumulation in KO mice. This was accompanied by pronounced increases in indices of skeletal muscle mitochondrial oxidative metabolism in KO mice. Together, these results show that hepatic gluconeogenesis is dispensable for exercise training to reduce liver lipids. This may be due to responses in ketone body metabolism and/or metabolic adaptations in skeletal muscle to exercise.

physiology↗