Metabolic disorders are characterized by an overall state of inflammation and oxidative stress, which highlight the importance of a functional antioxidant system and normal activity of some endogenous enzymes, namely paraoxonase-1 (PON1). PON1 is an antioxidant and anti-inflammatory glycoprotein from the paraoxonases family. It is mainly expressed in the liver and secreted to the bloodstream, where it binds to HDL. Although it was first discovered due to its ability to hydrolyze paraoxon, it is now known to have an antiatherogenic role. Recent studies have shown that PON1 plays a protective role in other diseases that are associated with inflammation and oxidative stress, such as Type 1 and Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease. The aim of this review is to elucidate the physiological role of PON1, as well as the impact of altered PON1 levels in metabolic disorders.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most prevalent cause of liver disease worldwide and afflicts adults and children as currently associated with obesity and insulin resistance. Even though lately some advances have been made to elucidate the mechanism and causes of the disease much remains unknown about NAFLD. The aim of this paper is to discuss the present knowledge regarding the pathogenesis of the disease aiming at the initial steps of NAFLD development, when inflammation impinges on fat liver deposition. At this stage, the Kupffer cells attain a prominent role. This knowledge becomes subsequently relevant for the development of future diagnostic, prevention, and therapeutic options for the management of NAFLD.

Glycated haemoglobin (HbA1c) is currently the gold standard for glucose monitoring in patients with diabetes, and has been increasingly adopted as a criteria for diabetes diagnosis. However, conditions that determine alterations in haemoglobin metabolism can interfere with the reliability of HbA1c measurements. Glycated albumin and fructosamine (total glycated serum proteins) are alternative markers of glycaemia, which have been recognised to provide additional information to HbA1c or to provide a reliable measure when HbA1c is observed not to be dependable. Additionally, while HbA1c monitors the exposure to circulating glycaemia in the previous 3 months, glycated albumin and fructosamine represent exposure for a shorter period, which may be beneficial to monitor rapid metabolic alterations or changes in diabetes treatment. The present review further discusses the relative value of HbA1c, glycated albumin, and fructosamine, in prediabetes and diabetes diagnosis, evaluation of glucose variability, and complications risk prediction. Also, a novel molecular role for albumin is presented by which glycated albumin contributes to glucose intolerance development and thus to progression to diabetes, besides the role of glycated albumin as a pro-atherogenic factor.

Obesity is a major risk factor for developing nonalcoholic fatty-liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty-liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity due to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiologic significance, hepatic ROCK1 was markedly up-regulated in humans with fatty-liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1-AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used anti-diabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1-AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.