br Available treatment modalities for individuals with NAFLD

Available treatment modalities for individuals with NAFLD There are several treatment modalities currently used or in clinical trials for individuals with NAFLD. The most widely recommended treatment is a lifestyle modification plan. As little as 5% weight loss has been shown to improve NASH histology in a pilot study of 23 overweight/obese subjects with biopsy-proven NASH. In another study, 31 overweight/obese individuals with biopsy-proven NASH were randomized to intensive lifestyle therapy or structured education. The patients in the intensive arm lost significantly more weight which led to improvement in steatosis, necrosis and inflammation. A more recent study documented improvement in all histologic features of NAFLD with weight loss, including fibrosis. Several studies have examined weight loss via bariatric surgery and have found improvement in hepatic steatosis, inflammation, and fibrosis. Additionally, exercise alone without any dietary intervention has been shown to decrease hepatic liver lipids and improve overall metabolic health. Hepatic staining of malondialdehyde and Cyp2E1 protein content decreased with surgical weight loss in obese subjects with NAFLD. A major limitation of lifestyle modification in the treatment of NASH is patient adherence, which can be as low as 30%. The next most common treatment is insulin-sensitizing agents. Several different insulin-sensitizing agents have been used to treat steatohepatitis with varying degrees of success. Although initial proof-of-concept studies have shown that metformin may be associated with histologic and biochemical improvement in NASH, subsequent larger studies failed to demonstrate histological benefit for metformin in patients with NASH. Pioglitazone, another insulin-sensitizing agent, resulted in decreased Tianeptine sodium australia and resolution of steatohepatitis when administered for 12–24months in non-diabetic subjects with NASH. Both PPAR-γ and PPAR-α agonistic effects of pioglitazone are believed to aid in its effect on NASH. However, pioglitazone is associated with higher rates of congestive heart failure and this concern has limited its widespread use in treatment of NASH. Likewise, while vitamin E (α-tocopherol) at a dose of 800IU/day has been shown to improve NASH histology in non-diabetic adults with biopsy-proven NASH, data regarding association of high-dose vitamin E with prostate cancer has to be cautiously considered and discussed with patients before long-term use. Analysis in vitro showed that α-tocopherol reduces lipoxygenase dependent peroxidation of pig liver phosphatidylcholine micelles. Several other agents are also being actively studied for NAFLD. A multicenter clinical trial showed that 6-ethylchenodeoxycholic acid (obeticholic acid), an activator of farsenoid X nuclear receptor (FXR), significantly improved steatohepatitis histopathology. Contrary to expectations, subjects treated with obeticholic acid also witnessed worsening HOMA-IR and an increase in mean total cholesterol and LDL fraction and a decrease in HDL fraction. The long-acting glucagon-like-peptide-1 agonist Liraglutide was shown to resolve NASH without progression of fibrosis in a significant number of subjects compared to placebo in a recently-published phase 2 trial (LEAN trial). In addition, the Liraglutide group showed significant decreases in hemoglobin A1C, absolute weight, BMI and increase in HDL cholesterol fraction, thus aiding cardiovascular risk optimization in this patient cohort. Based on both the limitations of the current available treatments and the molecular mechanisms of NAFLD, there are compelling reasons to study novel therapeutic interventions based on the 12-LOX/12-HETE signaling pathway. Protection of HFD-fed Alox15−/− mice from ER stress and inflammation described above suggests that interventions that inhibit 12-LOX with small molecule inhibitors, such as ML127, ML351 and ML355 would serve to protect these animals from steatohepatitis. Further studies are needed to confirm the potential of these proposed interventions, particularly given the possibility of off-target effects and non-tissue-specific effects of small molecule drugs of this nature.