Summary Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were studied using 2H and 13C tracers to evaluate systemic lipolysis, hepatic glucose production, and mitochondrial pathways (TCA cycle, anaplerosis, and ketogenesis). Individuals with NAFLD had 50% higher rates of lipolysis and 30% higher rates of gluconeogenesis. There was a positive correlation between IHTG content and both mitochondrial oxidative and anaplerotic fluxes. These data indicate that mitochondrial oxidative metabolism is ∼2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage.

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Summary Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 minutes after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.

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Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world. It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma. Its pathogenesis is complex, and involves a state of 'lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a 'lipotoxic liver disease' and its progression to NASH. The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established. A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other). Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis. However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis. The treatment of NASH requires a multifaceted approach. The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention. Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials. This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH.

The hepatic tricarboxylic acid (TCA) cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by(13)C-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry-based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P< 0.05) of mitochondrial fluxes (μmol/min) through the TCA cycle (2.6 ± 0.5 vs. 5.4 ± 0.6), anaplerosis (9.1 ± 1.2 vs. 16.9 ± 2.2), and pyruvate cycling (4.9 ± 1.0 vs. 11.1 ± 1.9) compared with their age-matched controls. Induction of the TCA cycle activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcarnitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA cycle failed to prevent accretion of "lipotoxic" metabolites in the liver and could hasten inflammation and the metabolic transition to NASH.

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