Biology subjects

Hampton, G. S.

Publications and source records attributed to Hampton, G. S..

3 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↗

bioRxiv2026

Hepatic ketogenesis supports liver lipid homeostasis during acute exercise but is not required for exercise training to mitigate liver steatosis in mice

The acceleration of hepatic lipid disposal during acute exercise has been proposed as a contributor to the anti-steatotic effects of exercise training. Ketogenesis, which produces acetoacetate (AcAc) and {beta}-hydroxybutyrate ({beta}OHB) from fatty acids, is among the lipid disposal pathways stimulated by exercise. This study tested the hypothesis that hepatic ketogenesis is necessary for exercise training to lower liver lipids. Liver-specific 3-hydroxymethylglutaryl-CoA synthase 2 knockout (HMGCS2 KO) mice and wild type (WT) littermates underwent sedentary, acute exercise, and exercise training protocols. Liver ketone bodies and lipids were determined via mass spectrometry platforms. Stable isotope infusions in conscious, unrestrained mice defined mitochondrial oxidative fluxes at rest and during exercise. Loss of hepatic HMGCS2 decreased liver AcAc and {beta}OHB concentrations and impaired their increase during exercise. Liver triacylglycerides (TAGs) were comparable between genotypes at rest (i.e., ad libitum fed and short fasted conditions). In contrast, liver TAGs were elevated in HMGCS2 KO mice following acute, non-exhaustive exercise. Liver TCA cycle flux was higher in KO mice at rest. During exercise, TCA cycle flux increased in both WT and KO mice but was not different between genotypes with greater exercise duration. This suggests that enhanced disposal of lipids via the TCA cycle may prevent liver lipid accumulation in HMGCS2 KO mice under sedentary conditions, but not during exercise. Unexpectedly, exercise training decreased liver TAGs similarly in both HMGCS2 KO and WT mice. In conclusion, hepatic ketogenesis supports liver lipid homeostasis during acute exercise, but is not required for exercise training to lower liver lipids. NEW & NOTEWORTHYExercise training has been proposed to mitigate liver steatosis partly through enhanced hepatic lipid disposal. During acute exercise, the disposal of fatty acids to ketone bodies is stimulated. This study tested the hypothesis that hepatic ketogenesis was required for exercise training to reduce liver fat in mice. The results show that hepatic ketogenesis is needed to prevent lipid accumulation during acute exercise, but is not necessary for exercise training to lower liver lipids.

physiology↗

bioRxiv2025

Myelin Mapping in the Human Brain Using an Empirical Extension of the Ridge Regression Theorem

PurposeMyelin water fraction (MWF) mapping in the central nervous system is a topic of intense research activity. One framework for this requires parameter estimation from a decaying biexponential signal. However, this is often an ill-posed nonlinear problem resulting in unreliable parameter estimates. For linear least-squares (LLS) problems, the ridge regression theorem (RRT) shows that a Tikhonov regularization parameter exists that will reduce mean square error (MSE) in parameter estimates. We present and apply a nonlinear version of the RRT,{lambda} -NL-RR, to MWF mapping. MethodsFor simulated and experimental data, we estimated parameter values with conventional nonlinear least-squares (NLLS) and compared these with values obtained from{lambda} -NL-RR, with the regularization parameter value defined by generalized cross validation. We applied regularization only to signals identified as biexponential according to the Bayesian information criterion. ResultsUnder conditions of modest SNR and closely spaced exponential time constants in which conventional biexponential analysis methods yield particularly inaccurate results,{lambda} -NL-RR decreases MSE by ~10-15%. ConclusionRegularization of the NLLS parameter estimation problem for the biexponential model decreased MSE for simulated and in vivo MRI brain data. In addition, this work provides a general framework for regularization of a broad class of NLLS problems.

biophysics↗