Treatments and Disease Management

 Non-alcoholic fatty liver disease is estimated to affect about one-third of the American adult population and is believed to develop from two different hits: fat accumulation in hepatocytes and inflammation/ reactive oxygen damage leading to liver fibrosis. NAFLD research has investigated both hits in order to develop treatments to both prevent the onset of the disease and the progression to nonalcoholic steatohepatitis and cirrhosis. In the current state of NAFLD research, there are no FDA approved treatments. The primary treatment, as could be expected, is lifestyle modification. Weight loss through dieting and exercise is capable of reversing nonalcoholic steatohepatitis by decreasing both fat content in the liver and inflammation caused by fat accumulation (Li et al., 2014). Yet, weight loss is difficult to achieve and maintain which calls for safe drugs that can be used to ameliorate NAFLD.

A Role for Apple Peels in the Fight Against NAFLD

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PPARalpha activation leads to inhibition of SREBP-1c which inhibits acetyl-CoA carboxylase and fatty acid synthesis. PPARalpha activation also leads to the activation of carnitine palmitoyltransferase-I which leads to the breakdown of fatty acids by beta-oxidation. Therefore, ursolic acid activation of PPARalpha leads to prevents fatty acid  accumulation in hepatocytes, ameliorating the first hit of NAFLD.
Image taken from: Grabacka, Maja, and Krzysztof Reiss. 2008. “Anticancer Properties of PPARalpha-Effects on Cellular Metabolism and Inflammation.” PPAR Research 2008: 930705. doi:10.1155/2008/930705.

A recent study by Li et al. revealed that ursolic acid may be capable of reversing high fat diet-induced hepatic steatosis (2014). Ursolic acid is a natural pentacyclic triterpenoid carboxylic acid which is found in various plants including the peels of apples and can also be purchased as a supplement at drug stores (Li et al., 2014). Administration of ursolic acid to an obese mouse model revealed a reversal in hepatic steatosis in a dose-dependent manner as well as a marked decrease in liver fat accumulation (Li et al., 2014). In addition, ursolic acid decreased circulating levels of aspartate aminotransferase and alanine aminotransferase which are indicative of liver damage, signifying that ursolic acid decreased liver injury in HFD (high fat diet)-fed mice (Li et al., 2014). The anti-steatotic effects of ursolic acid are believed to be associated with a PPAR-α dependent pathway. PPAR-α stimulates the transcription of several genes involved in lipid metabolism including CPT-1, carnitine palmitoyltransferase I, which is the rate-limiting enzyme that transports long-chain fatty acids into the mitochondria for beta-oxidation. PPAR-α levels are known to be decreased in people with NAFLD and PPAR-α knockout mice develop severe steatohepatitis (Li et al., 2014). Knocking down PPAR-α in an obese mouse model prevented the anti-steatotic effects associated with administration of ursolic acid, confirming that ursolic acid acts through a PPAR-α dependent pathway (Li et al., 2014). Additionally, ursolic acid administration reversed the HFD-induced decrease in PPAR-α expression in the obese mouse model (Li et al., 2014). The research group also found that PPAR-α reduced the expression of SREBP-1c which decreases the expression of several lipid biosynthetic genes (Li et al., 2014). These results provide a novel role for ursolic acid administration as a potential therapeutic agent against the first hit of NAFLD by preventing increased fatty acid biosynthesis and increasing beta-oxidation of fatty acids.

Safe Sirt1 Agonists Needed to Prevent NAFLD Progression

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Sirt1 activation inhibits NFkB which decreases inflammatory cytokines leading to hepatic inflammation seen in NASH. Additionally, Sirt1 activates PGC1alpha which upregulates antioxidant enzymes, MnSOD and Nrf1, thereby reducing reactive oxygen damage in the liver. Therefore, Sirt1 activation leads to decreased hepatic inflammation by both inhibiting NFkB and activating antioxidant enzymes.
Image taken from: Pfluger, Paul T., Daniel Herranz, Susana Velasco-Miguel, Manuel Serrano, and Matthias H. Tschöp. 2008. “Sirt1 Protects Against High-fat Diet-induced Metabolic Damage.” Proceedings of the National Academy of Sciences 105 (28) ( 7–15): 9793–9798. doi:10.1073/pnas.0802917105. http://www.pnas.org/content/105/28/9793.

Sirtuins have also been investigated as potential mediators of hepatic inflammation, the second hit of NAFLD. Sirtuins have deacylase activity and Sirt1 agonists have prevented the progression of NAFLD in mice (Shao et al., 2014). Sirt1 acts to mediate hepatic inflammation by inhibiting the transcription factor NFkB which decreases the presence of inflammatory cytokines (Pfluger et al., 2008). Sirt1 activity also upregulates PGC1α which  increases the expression of MnSOD and Nrf1, both of which are antioxidants (Pfluger et al., 2008). Under levels of oxidative stress, Sirt1 function is disrupted by oxidative post-translational modifications leading to increased inflammation and reactive oxygen damage, thereby promoting the progression to NASH (Shao et al., 2014). If clinically safe Sirt1 agonists are created, they can be used to ameliorate inflammation and reactive oxygen damage in NAFLD.

Vitamin D Takes Down Hepatic Stellate Cells

Another body of research has been exploring the link between Vitamin D deficiency and the metabolic syndrome. Kwok et al. found that Vitamin D concentrations were lower in patients with NASH compared to those with hepatic steatosis (2013). Vitamin D has been linked to the inhibition of hepatic stellate cell proliferation (Kwok et al., 2013). HSCs are responsible for depositing collagen in the liver in response to proinflammatory cytokines. The deposition of collagen then leads to the fibrosis seen in NASH and cirrhosis (Kwok et al., 2013). In an in vivo murine model, Vitamin D administration demonstrated anti-fibrotic effects (Kwok et al., 2013). Further research needs to be done to elucidate whether Vitamin D administration can prevent liver fibrosis in the presence of fatty acid accumulation. Additionally, more clinical studies must be done to see whether Vitamin D supplementation has these effects in humans.

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