Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet–induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH. Conclusion: Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH. (HEPATOLOGY 2012;56:2199–2208)

Obesity is a major health problem in industrialized societies often associated with diabetes, insulin resistance, and hepatic steatosis. This review addresses the hypothesis that elongation of long-chain fatty acids family member 6 (Elovl6) has an important role in energy metabolism and insulin sensitivity. Elovl6 is a microsomal enzyme involved in the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons. Mice with targeted disruption in the gene for Elovl6 (Elovl6 ^−/−) are resistant to diet-induced insulin resistance despite their hepatosteatosis and obesity being similar to that of the wild-type mice. Protection against diet-induced insulin resistance in Elovl6 ^–/– mice is partially due to restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C ɛ, resulting in restoration of Akt phosphorylation. We suggest that inhibition of this elongase could be a new therapeutic approach for the treatment of insulin resistance, diabetes, cardiovascular disease, and other metabolic diseases.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL) activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα), has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα) in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine.

Increased hepatic lipid content is associated with hepatic as well as whole-body insulin resistance and is typical for individuals with type 2 diabetes mellitus. However, whether insulin resistance causes hepatic steatosis or whether hepatic steatosis per se reduces insulin sensitivity remains unclear. Multiple metabolic pathways lead to the development of hepatic steatosis, including enhanced free fatty acid release from adipose tissues (lipolysis), increased de novo fatty acid synthesis (lipogenesis), decreased mitochondrial β-oxidation and decreased very low-density lipoprotein secretion. Although the molecular mechanisms leading to the development of hepatic steatosis in the pathogenesis of type 2 diabetes mellitus are complex, several recent animal models have shown that modulating important enzymes involved in hepatic fatty acid and glycerolipid synthesis might be a key for treating hepatic insulin resistance. We highlight recent advances in the understanding of the molecular mechanisms leading to the development of hepatic steatosis and insulin resistance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00111.x, 2011).