Review Article: The Emerging Interplay Among the Gastrointestinal Tract, Bile Acids and Incretins in the Pathogenesis of Diabetes and Non-alcoholic Fatty Liver Disease

A. Zarrinpar; R. Loomba

Disclosures

Aliment Pharmacol Ther. 2012;36(10):909-921. 

In This Article

Non-alcoholic Fatty Liver Disease and Insulin Resistance

Alcohol consumption and metabolic syndrome are the two main causes of hepatic steatosis. However, there are many potential causes of hepatic steatosis, including abetalipoproteinemia, acute fatty liver of pregnancy, malnutrition and refeeding syndrome, medications (e.g. amiodarone, methotrexate, tamoxifen), and environmental hepatotoxins (e.g. wild mushroom poisoning).[99] Hepatic steatosis that is associated with metabolic syndrome is commonly called non-alcoholic fatty liver disease (NAFLD). Insulin resistance and obesity are associated with an increased risk of NAFLD.[100] In patients with NAFLD, the prevalence of obesity is 30%–100% and the prevalence of T2DM is 10–75%.[99] NAFLD is the most common cause of abnormal liver enzymes in the clinical population of the US and affects approximately 20% of the population.[101] In patients with NAFLD, the accumulation of triglycerides in hepatocytes can eventually develop into inflammation (non-alcoholic steatohepatitis [NASH]), fibrosis, cirrhosis and even hepatocellular carcinoma. The molecular and physiological changes that lead to NAFLD have been extensively studied and reviewed.[102,103] The current hypothesis for its development is that obesity and insulin resistance increase the release of free fatty acids (FFAs) from adipocytes.[104] Once these FFAs reach the liver, they are either oxidated to generate adenosine triphosphate (ATP) or esterified to produce triglycerides. Triglycerides either become part of very-low-density lipoprotein particles that are exported to the serum, or they are stored within the hepatocyte itself. Defects in any of these processes can result in excessive triglyceride accumulation in the hepatocyte and eventual cell damage and inflammation.

Emerging data suggest that hepatic insulin resistance and hepatic steatosis precede the development of T2DM.[105,106] Elevated serum alanine aminotransferase and fatty liver on ultrasound predict the occurrence of diabetes.[106,107] A low-calorie diet is the primary therapy for insulin resistance and hepatic steatosis. Moderate diet-induced weight loss (5–10% of body weight) can decrease hepatic triglyceride content, improve glycaemic control and improve hepatic and muscle insulin sensitivity.[108,109] A meta-analysis of randomised trials of treatments for NAFLD found that weight loss was safe and improved histological disease activity in NASH in a dose-dependent fashion.[110] However, more than 50% of patients failed to achieve target weight loss, and it remains unclear whether patients were able to maintain the weight loss.

Pioglitazone (Takeda Pharmaceutical Company Limited, Osaka, Japan), a thiazolidinedione, has also shown beneficial effects in patients with non-alcoholic steatohepatitis and impaired glucose tolerance or T2DM; in addition to metabolic improvements, treatment with pioglitazone was associated with reductions in hepatic fat content and corresponding improvements in histological findings.[111] Although an early meta-analysis of randomised trials for the treatment of NAFLD showed that thiazolidinediones improved histological steatosis and inflammation, but not fibrosis,[110] a later meta-analysis that only included randomised, placebo-controlled trials (and hence excluded two open-label trials) showed that there was also an improvement in fibrosis.[112] However, patients treated with thiazolinediones had significant weight gain.

There are also multiple randomised control trials suggesting a possible benefit of metformin in non-alcoholic steatohepatitis, in addition to its glycaemic effects in T2DM.[113–116] Three trials showed improvement in liver histology after treatment with metformin.[113,115,117] Thiazolidinediones and metformin have both been shown to phosphorylate liver kinase B1 (LKB1), which promotes its nuclear export. LKB1, in turn, activates adenosine monophosphate–activated protein kinase (AMPK) in the liver,[118,119] leading to inhibition of anabolic cellular processes such as hepatic lipogenesis and gluconeogenesis, in addition to stimulating catabolic processes such as glycolysis, fatty acid oxidation, and mitochondrial biogenesis.[119,120] It should be noted that more recent studies on metformin did not find a benefit in hepatic steatosis, serum markers or insulin resistance when compared with lifestyle modification.[121–123] However, these results remain controversial, as the studies were conducted in small populations, and there were differences in duration and dose of treatment, and variable time periods between pre- and posttreatment biopsies.[116]

In addition, enzymes that increase oxidation of FFAs, which can prevent accumulation of hepatic triglycerides, can play a role in the treatment of hepatic steatosis, obesity, and other associated metabolic disorders. AMPK tightly regulates mitochondrial long-chain fatty acid oxidation through the inhibition of acetyl-CoA carboxylase 2 (ACC2).[124] A product of ACC2 is malonyl-CoA, which is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT1), a mitochondrial membrane enzyme that controls beta-oxidation. Cardiac endothelial cells also oxidise fatty acids in a carnitine-dependent manner, suggesting that this enzyme plays a role in preventing inflammation and coagulation associated with metabolic syndrome and heart disease.[125] As a result, both CPT1 and ACC2 have become potential therapeutic targets.[126]

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