*Transcriptional Regulation by ERR and Its Role in NAFLD Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.109089*

processes contribute to liver steatosis. High fat diet (HFD) induces hyperinsulinemia and hyperglycemia concurrent with glucose intolerance and IR together with NAFLD. During HFD feeding, dietary lipids may directly contribute to steatosis in addition to stimulating *de novo* lipogenesis in the liver. High carbohydrate diet (HCD) feeding, on the other hand, induces liver steatosis via carbohydrate-induced *de novo* lipogenesis. In both diets that induce steatosis, ERRα, the dominant liver isoform of ERRs, is upregulated in the liver [84]. Interestingly, ERRα is also induced in the steatotic livers of EtOH diet fed mice, further indicating a potential role of ERRα in liver steatosis.

In addition to diet induction, steatosis develops in patients with metabolic syndromes, including obesity, IR and Diabetes [86, 87]. As high as 80% of T2D patients exhibit NAFLD/NASH in the liver [87, 90]. Under these pathological conditions, abnormal insulin signals also contribute to liver lipid buildup in addition to the excess lipid and carbohydrate content coming from the diet. In obese individuals and particularly individuals with IR, "selective hepatic insulin resistance" is observed [91], where hyperinsulinemia cannot suppress hepatic gluconeogenesis (resistance) but continues to induce lipogenesis (non-resistance), leading to steatosis in the liver. Previous studies have established that insulin regulates *de novo* lipogenesis by activating phosphoinositide 3-kinases (PI3Ks), lipid kinases involved in the PI3K/AKT/ mammalian target of rapamycin (mTOR) signaling [92]. In the livers, loss of PTEN expression, a negative regulator of PI3K/AKT, leads to *de novo* lipogenesis and NAFLD development [93, 94]. Loss of AKT2 resulted in attenuation of lipid and blocked NAFLD development [95–97].

Evidence suggests that the PI3K/AKT signal induces CREB cyclic AMP (cAMP) response element-binding protein) to activate ERRα and mitochondrial biogenesis and bioenergetics in the hepatocytes [72, 98]. AKT was found to directly phosphorylate CREB at Ser133 as CREB contains a RXX(S/T) sequence that is a potential AKT substrate motif72. CREB is a 43 kDa basic/leucine zipper transcription factor expressed in most tissues. It is suggested to control the expression of over 4000 genes [99], including genes involved in regulation of hepatic glucose and lipid metabolism [100, 101]. Here, PGC-1 was found to be necessary for CREB to induce the gluconeogenesis program [101]. Notably, mice deficient in CREB function are prevented from hepatic lipid accumulation in models of metabolic syndromes such as the Zucker Rat, ob/ob mice, STZ induced T2D, as well as HFD-induced NAFLD [102]. However, loss of CREB function also led to fatty liver development in unchallenged mice [100]. The divergent response of CREB-ERRα regulation in hepatocytes where PI3K/AKT is active vs. inactive may be responsible for this paradoxical observation with CREB deficiency [72]. Consistent with this idea, mice deficient for ERRα (*Esrra*−/− mice) have been reported to be resistant to HFD-induced obesity and steatosis in the liver even though ERRα promotes a catabolic metabolic program [26].

It has been suggested that in addition to promoting TG breakdown during refeeding, ERRα also promotes TG buildup during chronic conditions [84, 103]. In NAFLD induced by rapamycin treatment, however, lack of ERRα was shown to impair fatty acid oxidation, while buildup of citrate due to downregulation of the TCA cycle is redirected towards lipid biosynthesis [83]. Thus, unexplored transcriptional roles of ERRs, at least ERRα in lipid biosynthesis vs. β-oxidation, likely play a role in the *in vivo* phenotype observed with ERR function under these different metabolic conditions. Indeed, in addition to the well characterized target MCAD, lipogenic genes are among the list of lipid metabolic genes that ERR regulates in data collected from a ChIP study, suggesting potential function of ERRs in lipid biosynthesis [44].
