Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

Objective: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR, defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans.

Design: Cross-sectional study in men and women across a range of adiposity.

Methods: Medication-free participants (n = 177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy.

Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.

Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C).

Indirect Calorimetry-Based Novel Approach for Evaluating Metabolic Flexibility and Its Association with Circulating Metabolic Markers in Middle-Aged Subjects.

We propose a novel method for assessing metabolic flexibility (MF) through indirect calorimetry. A total of twenty healthy volunteers (10 females; 10 males) aged 45-65 were categorized into a Low-Intensity activity group (LI, 0-1 session of 1 h per week) and a High-Intensity activity group (HI, 5-6 sessions of 2 h per week). Volunteers underwent a stepwise exercise test on a cycle ergometer, connected to a calorimeter, to examine respiratory gas exchange to evaluate peak fatty acid Oxidation (PFO) and peak carbohydrate oxidation (PCO).

Hepatocyte mARC1 promotes fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 () have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear.

MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies.

Background And Aim: Enhanced hepatic de novo lipogenesis (DNL) has been proposed as an underlying mechanism for the development of NAFLD and insulin resistance. Max-like protein factor X (MLX) acts as a heterodimer binding partner for glucose sensing transcription factors and inhibition of MLX or downstream targets has been shown to alleviate intrahepatic triglyceride (IHTG) accumulation in mice. However, its effect on insulin sensitivity remains unclear.

Determining the temporal, dose, and composition effects of nutritional substrates in an in vitro model of intrahepatocellular triglyceride accumulation.

Pathological accumulation of intrahepatic triglyceride underpins the early stages of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and cancer of the liver. Studies in humans suggest that consumption of a diet enriched in saturated compared to unsaturated fatty acids (FAs), is more detrimental to liver fat accumulation and metabolism. However, the reasons for the divergence remain unclear and physiologically-relevant cellular models are required.

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis.

Objective: Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans.

Soat2 ties cholesterol metabolism to β-oxidation and glucose tolerance in male mice.

Background: Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins.

Objectives: We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice.

Methods: Soat2 and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed.

Overfeeding Saturated Fat Increases LDL (Low-Density Lipoprotein) Aggregation Susceptibility While Overfeeding Unsaturated Fat Decreases Proteoglycan-Binding of Lipoproteins.

Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity.

Approach And Results: The participants (36 subjects; age, 48+/-10 years; body mass index, 30.

Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance.

Background: Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma () gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce.

Modifying nutritional substrates induces macrovesicular lipid droplet accumulation and metabolic alterations in a cellular model of hepatic steatosis.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) begins with steatosis, where a mixed macrovesicular pattern of large and small lipid droplets (LDs) develops. Since in vitro models recapitulating this are limited, the aims of this study were to develop mixed macrovesicular steatosis in immortalized hepatocytes and investigate effects on intracellular metabolism by altering nutritional substrates.

Methods: Huh7 cells were cultured in 11 mM glucose and 2% human serum (HS) for 7 days before additional sugars and fatty acids (FAs), either with 200 µM FAs (low fat low sugar; LFLS), 5.

Intrahepatic Fat and Postprandial Glycemia Increase After Consumption of a Diet Enriched in Saturated Fat Compared With Free Sugars.

Objective: Debate continues regarding the influence of dietary fats and sugars on the risk of developing metabolic diseases, including insulin resistance and nonalcoholic fatty liver disease (NAFLD). We investigated the effect of two eucaloric diets, one enriched with saturated fat (SFA) and the other enriched with free sugars (SUGAR), on intrahepatic triacylglycerol (IHTAG) content, hepatic de novo lipogenesis (DNL), and whole-body postprandial metabolism in overweight males.

Research Design And Methods: Sixteen overweight males were randomized to consume the SFA or SUGAR diet for 4 weeks before consuming the alternate diet after a 7-week washout period.

Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.

Hyperinsulinaemia: does it tip the balance toward intrahepatic fat accumulation?

In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health.

Effects on hepatic lipid metabolism in human hepatoma cells following overexpression of TGFβ induced factor homeobox 1 or 2.

Transforming growth factor β induced factor homeobox (TGIF) 1 and 2 are two transcriptional repressors. Although TGIF1 has been found to be involved in lipid metabolism, no studies have yet investigated the role of TGIF2 in hepatic lipid metabolism. Here we aim to investigate effects on hepatic lipid metabolism following overexpression of the human and mouse TGIF1 and TGIF2 protein.

In vitro cellular models of human hepatic fatty acid metabolism: differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum.

Human primary hepatocytes are the gold standard for investigating lipid metabolism in nonalcoholic fatty liver disease (NAFLD); however, due to limitations including availability and donor variability, the hepatoma cell lines Huh7 and HepG2 are commonly used. Culturing these cell lines in human serum (HS) has been reported to improve functionality; however, direct comparison of fatty acid (FA) metabolism in response to culturing in HS is lacking. The aim of this study was to compare FA metabolism between HepG2 and Huh7 cells in response to culturing in different sera.

Chylomicron-Derived Fatty Acid Spillover in Adipose Tissue: A Signature of Metabolic Health?

Context And Objectives: Spillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity.

Participants And Methods: Seventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs.

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication.

Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.

Background: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women.

Material And Methods: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ).

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults.

Resistance to the action of insulin affects fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver, and triglyceride export from the liver. To understand the metabolic consequences of hepatic fatty acid synthesis, partitioning, oxidation, and net liver fat content in the fasted and postprandial states, we used stable-isotope tracer methodologies to study healthy men and women with varying degrees of insulin resistance before and after consumption of a mixed meal. Subjects were classified as being normoinsulinemic (NI) (fasting plasma insulin <11.

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women.

Background: Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low-density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and postmenopausal women.

Methods And Results: We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.

Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men.

Context And Objective: In most populations a greater proportion of men have hepatic steatosis than women. Sex-specific differences in hepatic dietary fatty acid (FA) metabolism have not been well characterized. We compared fasting and postprandial hepatic FA synthesis (de novo lipogenesis [DNL]) and oxidation in men and women.

Lower resting and total energy expenditure in postmenopausal compared with premenopausal women matched for abdominal obesity.

The menopause is accompanied by increased risk of obesity, altered body fat distribution and decreased skeletal muscle mass. The resulting decrease in RMR should be accompanied by a compensatory change in energy balance to avoid weight gain. We aimed to investigate habitual energy intake and expenditure in pre- and postmenopausal women matched for abdominal obesity.