Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice.

Unlabelled: Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number.

Membrane-bound -acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.

Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive.

FOXS1 is increased in liver fibrosis and regulates TGFβ responsiveness and proliferation pathways in human hepatic stellate cells.

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs.

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice.

Background And Aims: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.

Approach And Results: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks.

Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice.

Background And Aims: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism.

Approach And Results: Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks.

Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake.

Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms.

Background: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.

Methods: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total).

Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation.

Background & Aims: The consumption of sugar and a high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD are largely elusive.

Methods: Six-week-old, male, C57Bl/6 J mice were fed either chow or a HFD and were provided with regular, fructose- or glucose-sweetened water.

Fructose impairs fat oxidation: Implications for the mechanism of western diet-induced NAFLD.

Increased fructose intake from sugar-sweetened beverages and highly processed sweets is a well-recognized risk factor for the development of obesity and its complications. Fructose strongly supports lipogenesis on a normal chow diet by providing both, a substrate for lipid synthesis and activation of lipogenic transcription factors. However, the negative health consequences of dietary sugar are best observed with the concomitant intake of a HFD.

Design and rationale for the supermarket and web-based intervention targeting nutrition (SuperWIN) for cardiovascular risk reduction trial.

Purpose: The prevalence of chronic diseases is increasing largely due to suboptimal dietary habits. It is not known whether individualized, supermarket-based, nutrition education delivered by registered dietitians, utilizing the advantages of the in-store and online environments, and electronically collected purchasing data, can increase dietary quality.

Methods And Results: The supermarket and web-based intervention targeting nutrition (SuperWIN) for cardiovascular risk reduction trial is a randomized, controlled dietary intervention study.

Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice.

There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested.

Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms.

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure.

A luminescence-based protocol for assessing fructose metabolism via quantification of ketohexokinase enzymatic activity in mouse or human hepatocytes.

Ketohexokinase (KHK) catalyzes the first step of fructose metabolism. Inhibitors of KHK enzymatic activity are being evaluated in clinical trials for the treatment of non-alcoholic fatty liver disease (NAFLD) and diabetes. Here, we present a luminescence-based protocol to quantify KHK activity.

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae.

Objective: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.

Tissue-Specific Fructose Metabolism in Obesity and Diabetes.

Purpose Of Review: The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD).

Recent Findings: Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake.

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression.

The goal of this study was to define the functional role of adipocyte-specific expression of the RNA binding protein Human antigen R (HuR). Mice with an adipocyte-specific deletion of HuR ( ) were generated by crossing HuR floxed ( ) mice with mice expressing adiponectin-driven cre-recombinase (). Our results show that mice display a lean phenotype compared to wild-type littermate controls.

Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism.

The gut microbe-derived metabolite trimethylamine--oxide (TMAO) has recently been linked to cardiovascular disease (CVD) pathogenesis, prompting the development of therapeutic strategies to reduce TMAO. Previous work has shown that experimental alteration of circulating TMAO levels via dietary alterations or inhibition of the host TMAO producing enzyme flavin containing monooxygenase 3 (FMO3) is associated with reorganization of host cholesterol and bile acid metabolism in mice. In this work, we set out to understand whether recently developed nonlethal gut microbe-targeting small molecule choline trimethylamine (TMA) lyase inhibitors also alter host cholesterol and bile acid metabolism.

Dietary Choline Supplementation Attenuates High-Fat-Diet-Induced Hepatocellular Carcinoma in Mice.

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Choline deficiency has been well studied in the context of liver disease; however, less is known about the effects of choline supplementation in HCC.

Objective: The objective of this study was to test whether choline supplementation could influence the progression of HCC in a high-fat-diet (HFD)-driven mouse model.

Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis.

Adipose tissue is classically recognized as the primary site of lipid storage, but in recent years has garnered appreciation for its broad role as an endocrine organ comprising multiple cell types whose collective secretome, termed as adipokines, is highly interdependent on metabolic homeostasis and inflammatory state. Anatomical location (e.g.