: Accumulation of cytoplasmic triacylglycerol (TG) underlies hepatic steatosis, a major cause of cirrhosis. The pathways of cytoplasmic TG metabolism are not well known in hepatocytes, but evidence suggests an important role in lipolysis for adipose triglyceride lipase (ATGL). We created mice with liver-specific inactivation of Pnpla2, the ATGL gene. These ATGLLKO mice had severe progressive periportal macrovesicular and pericentral microvesicular hepatic steatosis (73, 150, and 226 μmol TG/g liver at 4, 8, and 12 months, respectively). However, plasma levels of glucose, TG, and cholesterol were similar to those of controls. Fasting 3-hydroxybutyrate level was normal, but in thin sections of liver, beta oxidation of palmitate was decreased by one-third in ATGLLKO mice compared with controls. Tests of very low-density lipoprotein production, glucose, and insulin tolerance and gluconeogenesis from pyruvate were normal. Plasma alanine aminotransferase levels were elevated in ATGLLKO mice, but histological estimates of inflammation and fibrosis and messenger RNA (mRNA) levels of tumor necrosis factor-α and interleukin-6 were similar to or lower than those in controls. ATGLLKO cholangiocytes also showed cytoplasmic lipid droplets, demonstrating that ATGL is also a major lipase in cholangiocytes. There was a 50-fold reduction of hepatic diacylglycerol acyltransferase 2 mRNA level and a 2.7-fold increase of lipolysosomes in hepatocytes (P < 0.001), suggesting reduced TG synthesis and increased lysosomal degradation of TG as potential compensatory mechanisms. Conclusion: Compared with the hepatic steatosis of obesity and diabetes, steatosis in ATGL deficiency is well tolerated metabolically. ATGLLKO mice will be useful for studying the pathophysiology of hepatic steatosis. (HEPATOLOGY 2011;)

The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies. The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. Fatty liver is a major complication of obesity and of type 2 diabetes mellitus. It carries a high risk of cirrhosis and liver cancer. In fatty liver, triglycerides accumulate to high levels in the cytoplasm of hepatocytes. Triglycerides are degraded by lipolysis, which has been most studied in fat cells where its three steps are catalyzed by different enzymes. The second step, hydrolysis of diglyceride to a monoglyceride, can be mediated by hormone-sensitive lipase (HSL). Patients with genetic deficiency of HSL have fatty liver. In this study, we found that systemic HSL deficient mice developed fatty liver with aging. To study the mechanism of steatosis, we made liver-specific HSL-deficient mice. Surprisingly, these mice had normal liver fat content. We then studied mice with HSL deficiency in adipose tissue. Adipose HSL-deficient mice developed hepatic steatosis to a similar extent as mice with systemic HSL deficiency, showing that adipose HSL deficiency is sufficient to cause fatty liver. Furthermore, like reported HSL-deficient humans, mice with adipose HSL deficiency had systemic insulin resistance, reduced fat mass and inflammation in fat tissue. Each of these is known to promote hepatic steatosis. Livers of adipose HSL-deficient mice showed low levels of hepatic fatty acid (FA) oxidation, of very low density lipoprotein (VLDL) secretion and of triglycerides (TG) hydrolase activity, each of which could contribute to fat accumulation in liver. Tissue-selective genetic alterations may help in identifying and understanding the tissues responsible for complex metabolic phenotypes like fatty liver. Our data suggest that at least in mice, strategies for treatment of fatty liver related to HSL deficiency should concentrate on adipose tissue.

Glycerophospholipids (GPLs) are the main lipid components of cellular membranes. They are implicated in membrane structure, vesicle trafficking, neurotransmission, and cell signalling. GPL molecules are amphiphilic, organized around the three carbons of glycerol. Positions sn‐1 and sn‐2 are each esterified to a fatty acid (FA). At position sn‐3 , a phosphate group is linked, which in turn can bind a polar head group, the most prevalent classes being phosphatidic acid (PA, phosphate alone as head group), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). Pathways of GPL biosynthesis span several cell compartments (endoplasmic reticulum (ER), Golgi mitochondria). Particularly important are mitochondria‐associated membranes (MAMs), where the ER and mitochondrial outer membrane are in proximity. After synthesis, GPLs continuously undergo remodelling by FA hydrolysis and re‐esterification. Esterification with different FAs alters membrane properties. Many steps in GPL synthesis and remodelling can be mediated by more than one enzyme, suggesting complexity that requires further exploration. The 38 known GPL‐related inborn errors are clinically diverse. 23 (61%) have neurologic features, sometimes progressive and severe, particularly developmental delay/encephalopathy in 16 (42%) and spastic paraplegia in 12 (32%). Photoreceptor/neuroretinal disease occurs in 14 (37%). Three present skeletal dysplasias (8%). Most GPL inborn errors have been diagnosed by broad molecular testing. Lipidomics holds promise for diagnostic testing and for the discovery of functionally relevant metabolite profiles for monitoring natural history and treatment response.