Low carbohydrate and low-calorie diets reduce liver fat and lower brain glutamate and myo-inositol levels in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

In a longitudinal cohort study with intervention (NCT05216796), we utilized multiorgan imaging to determine if metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with elevated cerebral glutamate and myo-inositol and to determine their sensitivity to dietary intervention. Fifty-five adults with self-reported MASLD or high MASLD risk (3 + metabolic risk factors) received liver and brain magnetic resonance spectroscopy scans pre and post two-week low carbohydrate (≤30 g/d) or low-calorie (women ~ 1200 kcal/d; men ~ 1500 kcal/d) diet, both known for their ability to reduce liver fat. Forty-four adults completed the study (36 female, average age 54 years).

Weight loss in MASLD restores the balance of liver fatty acid sources.

BACKGROUNDLipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction-associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODSOverweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.

Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with nonalcoholic fatty liver.

BACKGROUNDHepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of nonalcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.

Associations of liver fat content with cardiometabolic phenotypes and outcomes in a multi-ethnic population: Results from the Dallas Heart Study.

Aims: To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression.

Methods: Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N = 2287) and at follow-up (N = 343) after a mean of 7.3 years.

Measurement of lipogenic flux by deuterium resolved mass spectrometry.

De novo lipogenesis (DNL) is disrupted in a wide range of human disease. Thus, quantification of DNL may provide insight into mechanisms and guide interventions if it can be performed rapidly and noninvasively. DNL flux is commonly measured by H incorporation into fatty acids following deuterated water (HO) administration.

In Vivo Estimation of Ketogenesis Using Metabolic Flux Analysis-Technical Aspects and Model Interpretation.

Ketogenesis occurs in liver mitochondria where acetyl-CoA molecules, derived from lipid oxidation, are condensed into acetoacetate (AcAc) and reduced to β-hydroxybutyrate (BHB). During carbohydrate scarcity, these two ketones are released into circulation at high rates and used as oxidative fuels in peripheral tissues. Despite their physiological relevance and emerging roles in a variety of diseases, endogenous ketone production is rarely measured in vivo using tracer approaches.

Dallas Steatosis Index Identifies Patients With Nonalcoholic Fatty Liver Disease.

Background & Aims: Tools have been developed to determine risk for nonalcoholic fatty liver disease (NAFLD) based on imaging, which does not always detect early-grade hepatic steatosis. We aimed to develop a tool to identify patients with NAFLD using H MR spectroscopy (MRS).

Methods: We collected data from the Dallas Heart Study-a multiethnic, population-based, probability study of adults (18-65 y) that comprised an in-home medical survey; collection of fasting blood samples; MRS images to measure cardiac mass/function, abdominal subcutaneous/visceral adiposity; and quantification of hepatic triglyceride concentration, from 2000 through 2009.

Simultaneous tracers and a unified model of positional and mass isotopomers for quantification of metabolic flux in liver.

Computational models based on the metabolism of stable isotope tracers can yield valuable insight into the metabolic basis of disease. The complexity of these models is limited by the number of tracers and the ability to characterize tracer labeling in downstream metabolites. NMR spectroscopy is ideal for multiple tracer experiments since it precisely detects the position of tracer nuclei in molecules, but it lacks sensitivity for detecting low-concentration metabolites.

Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, and potentially morbid, disease that affects one-third of the U.S. population.

Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver.

The hepatic TCA cycle supports oxidative and biosynthetic metabolism. This dual responsibility requires anaplerotic pathways, such as pyruvate carboxylase (PC), to generate TCA cycle intermediates necessary for biosynthesis without disrupting oxidative metabolism. Liver-specific PC knockout (LPCKO) mice were created to test the role of anaplerotic flux in liver metabolism.

Crohn's Disease Is Associated With an Increased Prevalence of Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study Using Magnetic Resonance Proton Density Fat Fraction Mapping.

Nonalcoholic fatty liver disease (NAFLD) commonly coexists with Crohn's disease (CD); however, it remains unclear if it is more prevalent than would be expected as ultrasound surveys of CD patients report a very wide range of prevalence (9%-40%). To address this uncertainty, we performed a prospective, cross-sectional survey of NAFLD in CD patients by generating magnetic resonance proton density fat fraction (MR-PDFF) maps as compared with 2 control populations. MR-PDFF provides a quantitative, sensitive and specific (97% and 100%, respectively) radiographic surrogate for liver fat.

Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting 75-100 million Americans. However, the disease burden may not be equally distributed among races or ethnicities. We conducted a systematic review and meta-analysis to characterize racial and ethnic disparities in NAFLD prevalence, severity, and prognosis.

Influence of liver triglycerides on suppression of glucose production by insulin in men.

Context: The ability of insulin to suppress hepatic glucose production is impaired among subjects with increased intrahepatic triglycerides (IHTG). However, little is known about the roles of insulin on the supporting fluxes of glucose production among patients with fatty liver.

Objective: To evaluate the effects of insulin on fluxes through the three potential sources of plasma glucose (glycerol, the citric acid cycle, and glycogen) among patients with fatty liver.

Fat and iron quantification in the liver: past, present, and future.

Liver fat, iron, and combined overload are common manifestations of diffuse liver disease and may cause lipotoxicity and iron toxicity via oxidative hepatocellular injury, leading to progressive fibrosis, cirrhosis, and eventually, liver failure. Intracellular fat and iron cause characteristic changes in the tissue magnetic properties in predictable dose-dependent manners. Using dedicated magnetic resonance pulse sequences and postprocessing algorithms, fat and iron can be objectively quantified on a continuous scale.

Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.

Background & Aims: There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls).

Methods: We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat.