Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin.

The processes causing increased hepatic triglycerides (TGs) in mouse models of hepatic steatosis (HS) due to high fat diet (HFD)-induced obesity (DIO), EtOH consumption, or obesity mutations () are uncertain. This report summarizes two studies. Study 1 focused on regulation by five transcription factors (TFs) (NfKb, Srebp-lc, AMPK, PPARα, PPARγ) of seven, much-studied hepatic long-chain fatty acid (LCFA) transporters (FABPpm, CD36, FATPl, FATP2, FATP4, FATP5, & Caveolin-1 [CAV-1]), and expression of genes for enzymes of LCFA synthesis (SCD-1, FASN) in mice with HS from various causes.

Nonalcoholic Fatty Liver Disease: Lipids and Insulin Resistance.

Obesity and its major comorbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, have caused life expectancy in the United States to decline in recent years. Obesity is the increased accumulation of triglycerides (TG), which are synthesized from glycerol and long-chain fatty acids (LCFA) throughout the body. LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes.

Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss.

Objective: This study examined whether changes in adipocyte long chain fatty acid (LCFA) uptake kinetics explain the weight regain increasingly observed following bariatric surgery.

Methods: Three groups (10 patients each) were studied: patients without obesity (NO: BMI 24.2 ± 2.

Hepatic pathology among patients without known liver disease undergoing bariatric surgery: observations and a perspective from the longitudinal assessment of bariatric surgery (LABS) study.

Liver biopsy is not routine during bariatric surgery. Alanine aminotransferase (ALT) is widely used to screen for liver disease. We assessed the relationship between ALT and pathology in biopsies from Longitudinal Assessment of Bariatric Surgery (LABS) patients with normal preoperative ALTs.

Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity.

Objective: Microarray studies identified Ch12:orf39 (Spexin) as the most down-regulated gene in obese human fat. Therefore, we examined its role in obesity pathogenesis.

Methods: Spexin effects on food intake, meal patterns, body weight, respiratory exchange ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with diet-induced obesity (DIO).

Metabolic syndrome prevalence and associations in a bariatric surgery cohort from the Longitudinal Assessment of Bariatric Surgery-2 study.

Background: Metabolic syndrome is associated with higher risk for cardiovascular disease, sleep apnea, and nonalcoholic steatohepatitis, all common conditions in patients referred for bariatric surgery, and it may predict early postoperative complications. The objective of this study was to determine the prevalence of metabolic syndrome, defined using updated National Cholesterol Education Program criteria, in adults undergoing bariatric surgery and compare the prevalence of baseline co-morbid conditions and select operative and 30-day postoperative outcomes by metabolic syndrome status.

Methods: Complete metabolic syndrome data were available for 2275 of 2458 participants enrolled in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2), an observational cohort study designed to evaluate long-term safety and efficacy of bariatric surgery in obese adults.

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis.

CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36-deficient (Cd36(-/-)) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36(-/-) mice would be resistant to alcoholic steatosis.

Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity.

Importance: Severe obesity (body mass index [BMI] ≥35) is associated with a broad range of health risks. Bariatric surgery induces weight loss and short-term health improvements, but little is known about long-term outcomes of these operations.

Objective: To report 3-year change in weight and select health parameters after common bariatric surgical procedures.

Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease.

Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease.

Chronic ethanol consumption increases cardiomyocyte fatty acid uptake and decreases ventricular contractile function in C57BL/6J mice.

Alcohol, a major cause of human cardiomyopathy, decreases cardiac contractility in both animals and man. However, key features of alcohol-related human heart disease are not consistently reproduced in animal models. Accordingly, we studied cardiac histology, contractile function, cardiomyocyte long chain fatty acid (LCFA) uptake, and gene expression in male C57BL/6J mice consuming 0, 10, 14, or 18% ethanol in drinking water for 3months.

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.

Background & Aims: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling.

Methods: Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks.

Reporting weight change: standardized reporting accounting for baseline weight.

Background: Although it is recognized that a standardized approach to reporting weight change is essential to meaningful comparisons among cohorts and across studies, consensus is lacking. This study aimed to propose a method of reporting weight change that would allow meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS).

Methods: Relationships among several measures of weight change are described.

Cardiomyocyte triglyceride accumulation and reduced ventricular function in mice with obesity reflect increased long chain Fatty Acid uptake and de novo Fatty Acid synthesis.

A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD) and db/db and ob/ob mice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers.

Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage.

Unlabelled: Hepatic stellate cell (HSC) lipid droplets are specialized organelles for the storage of retinoid, accounting for 50-60% of all retinoid present in the body. When HSCs activate, retinyl ester levels progressively decrease and the lipid droplets are lost. The objective of this study was to determine if the HSC population in a healthy, uninjured liver demonstrates heterogeneity in its capacity for retinoid and lipid storage in lipid droplets.

Thirty-day mortality after bariatric surgery: independently adjudicated causes of death in the longitudinal assessment of bariatric surgery.

Background: Mortality following bariatric surgery is a rare event in contemporary series, making it difficult for any single center to draw meaningful conclusions as to cause of death. Nevertheless, much of the published mortality data come from single-center case series and reviews of administrative databases. These sources tend to produce lower mortality estimates than those obtained from controlled clinical trials.

Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study.

Chronic alcohol consumption is associated with fatty liver disease in mammals. The object of this study was to gain an understanding of dysregulated lipid metabolism in alcohol-fed C57BL/6 mice using a targeted lipidomic approach. Liquid chromatography tandem mass spectrometry was used to analyze several lipid classes, including free fatty acids, fatty acyl-CoAs, fatty acid ethyl esters, sphingolipids, ceramides, and endocannabinoids, in plasma and liver samples from control and alcohol-fed mice.

Molecular modeling and functional confirmation of a predicted fatty acid binding site of mitochondrial aspartate aminotransferase.

Molecular interactions are necessary for proteins to perform their functions. The identification of a putative plasma membrane fatty acid transporter as mitochondrial aspartate aminotransferase (mAsp-AT) indicated that the protein must have a fatty acid binding site. Molecular modeling suggests that such a site exists in the form of a 500-Å(3) hydrophobic cleft on the surface of the molecule and identifies specific amino acid residues that are likely to be important for binding.

Digital analysis of hepatic sections in mice accurately quantitates triglycerides and selected properties of lipid droplets.

We describe a method for the histologic evaluation of lipid accumulation in the livers of various mouse models of hepatic steatosis based on quantitative digital analysis of Oil Red O (ORO) accumulation in fresh-frozen hepatic sections. The process involves two principal steps: identification and digital photographic imaging of areas appropriate for analysis, followed by digital determination of the fraction of the identified area (Area Fraction) exhibiting ORO staining. The Area Fraction, designated the Digital Steatosis Score, is a valuable aspect of the histologic assessment of the liver, especially in various forms of alcoholic and non-alcoholic liver diseases.

Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice.

Hepatic steatosis results from several processes. To assess their relative roles, hepatocellular long-chain fatty acid (LCFA) uptake was assayed in hepatocytes from C57BL/6J control mice, mice with steatosis from a high-fat diet (HFD) or 10%, 14%, or 18% ethanol (EtOH) in drinking water [functioning leptin-signaling groups (FLSGs)], and ob/ob and db/db mice. V(max) for uptake was increased vs.