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In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.

Background/Objective Although assumed, it remains unclear that fatty acid (FA) biomarkers of n-3 long-chain PUFA reflect wide ranges of intake. However, to be utilised as biomarkers, to predict dietary intake, dose-response curves that cover a spectrum of intakes are required. The aim of the study was to investigate whether the FA composition of plasma phosphatidylcholine (PC) is a sensitive biomarker of n-3 FAs from fish oil, across a range of supplementation doses, and alpha-linolenic acid (ALA) supplementation, in young, healthy women. Subjects/Methods A total of 303 young women were randomized to intakes ranging between 0.33 and 4.50 g EPA+DHA/day from fish oil (not all doses used in each year) or flaxseed oil (5.90–6.60 g/day) daily for 14 days in a series of trials, over five years. Fasting blood was collected at baseline (Day 0) and day 14 and plasma PC FA composition, total and HDL-cholesterol and triacylglycerol concentrations measured. Results Fourteen days supplementation with fish oil significantly (P Conclusion Our data demonstrate plasma PC is a sensitive biomarker of n-3 FA intake and reflects changes within 14 days across a range of intakes.

Upper-body adiposity is associated with increased metabolic disease risk, whilst lower-body adiposity is paradoxically protective. Efforts to understand the underlying mechanisms require appropriate and reproducible in vitro culture models. We have therefore generated immortalised (im) human preadipocyte (PAD) cell lines derived from paired subcutaneous abdominal and gluteal adipose tissue. These cell lines, denoted imAPAD and imGPAD display enhanced proliferation and robust adipogenic capacities. Differentiated imAPAD and imGPAD adipocytes synthesise triglycerides de novo and respond lipolytically to catecholamine-stimulation. Importantly the cells retain their depot-of-origin ‘memory’ as reflected by inherent differences in fatty acid metabolism and expression of depot-specific developmental genes. These features make these cell lines an invaluable tool for the in vitro investigation of depot-specific human adipocyte biology.

Obstructive sleep apnoea (OSA) is characterised by repeated cycles of reduced and complete obstruction of air flow occurring in sleep. This can result in decreased oxygen levels (hypoxia). OSA and states of glucocorticoid excess are both associated with metabolic diseases including fatty liver disease. Whether increased glucocorticoids are a feature of OSA and may contribute to the increased metabolic risk seen in OSA is unknown. In vitro, patient and healthy volunteer studies were employed to assess adipose response to hypoxia. Further metabolic effects of acute and chronic intermittent hypoxia (AIH and CIH) were examined in healthy volunteers and rodents respectively. The AIH study incorporated glucocorticoid receptor (GR) blockade. The patient study also examined the effect of OSA on glucocorticoid availability. Adipocytes were sensitive to extreme hypoxia in vitro although this was not seen in adipose biopsies from patients with OSA or in assessment of adipose function in AIH. AIH in man and CIH in rodents resulted in increased de novo lipogenesis (DNL). Sham CPAP was associated with increased urinary glucocorticoids. GR blockade limited adipose tissue fatty acid mobilisation but did not affect the metabolic impact of AIH on DNL. Intermittent hypoxia drives DNL. OSA is associated with increased glucocorticoids. Despite this GR blockade was not protective against the effects of intermittent hypoxia in this model and is unlikely to be a useful therapeutic target therefore in patients with OSA.

In 2008, Cecilia Kell, an indigenous woman from the Behchokǫ̀ community in Canada’s Northwest Territories (NWT), submitted a complaint to the Committee on the Elimination of Discrimination against Women (‘CEDAW Committee’). Over a decade earlier, Kell had been living in a common-law relationship with her partner, William Senych. Together, they had lived in housing specially set aside for indigenous people, allocated by the Northwest Territories Housing Corporation. Senych himself was not indigenous. Senych was abusive, and Kell was forced from their home on multiple occasions. On one occasion, she returned to find the locks changed, and to discover that Senych, who was a member of the Community’s housing board, had exploited his position on the board to have her name removed from the title to the property. Over the next 11 years, Kell struggled to regain her home. In multiple engagements with the Canadian legal system, many of them mediated through state-provided legal aid lawyers, Kell found the law deaf to her claims. As a marginalised person seeking to be audible to the law, her struggles reveal the almost Kafkaesque nature of legal engagements for marginalised actors. Her legal aid lawyers advised her not to contest her forced removal from the home. They pursued compensation while she sought restitution of the home itself. They acted contrary to her instructions. The lack of independent funds to pursue her case hampered her. Her claims were dismissed without written reasons. Throughout, however, she remained committed to one aim: regaining her home. Although the CEDAW Committee found in Kell’s favour, our re-written decision is motivated by a number of issues that we perceive to be problematic with the CEDAW views in this case from a feminist perspective. Notably, the CEDAW Committee’s decision hints at, but fails to fully expose, the multiple ways in which the law marginalised and silenced Cecilia Kell. The decision reveals a failure to grasp the intersectional nature of the discrimination that Kell experienced, and its impact on her ability to pursue her legal claims. More particularly, we were unsatisfied with the construction and application of some of the CEDAW provisions, notably on the right to housing, the right to independently conclude a contract, and on women’s property ownership. We were also surprised that the Committee did not pay more attention to Kell’s indigeneity and the fact that the loss of her housing had resulted from abuse suffered in the home. The Kell case is representative of the problems that face marginalised women when they seek to assert their rights both in domestic legal contexts, and indeed under CEDAW. As such, we have re-written this decision to make evident the ways in which the law can silence or render the claims of women invisible. But also to demonstrate how the law – and specifically CEDAW – can, using alternative (and importantly, feminist) methodologies, hear and see them. Our work here is informed by insights from film theory, particularly the concept of the ‘space

Considerations of legal pluralism and human rights do not go readily hand in hand – on the face of it, they appear to have different core concerns and motivations, with the former being conceptual in character while the latter is normative. This chapter argues, however, that a reading of human rights as being solely about universal norms is an overly narrow one, and that a more nuanced approach – one that reflects upon the operation of human rights norms within varied, co-existing and overlapping legal regimes – is required. It employs the International Court of Justice (ICJ) case of the Bakassi Peninsula (2002) as grounds on which to consider fertile intersections of legal pluralism and human rights, with a focus on two particular issues: first, the challenge of addressing contemporary border disputes that can trace their origins to colonialisation, and; second, the matter of human rights’ effectiveness in producing changes to international legal mechanisms and practices. In choosing an ICJ case as its study, this chapter draws attention to the purportedly neutral definitions, practices and forums that permeate both international law and international human rights law, and presents legal pluralism as a vital resource in both recognising and combatting such default settings.

Increased consumption of foods containing free sugars, especially fructose, has been associated with the development of non-alcoholic fatty liver disease (NAFLD). The overall aim of this thesis is to investigate the effect of composition of fructose and glucose on hepatic fatty acid (FA) synthesis and partitioning and insulin response and to do this, three studies were undertaken. A randomised crossover study was conducted, where subjects consumed a low fructose meal and a high fructose meal with [U13C]palmitate incorporated to trace the metabolic fate of dietary fats. The two study visits were four weeks apart. Overall, it was found that consuming a high fructose meal but not a low fructose one had a marked effect on females but not males in postprandial hepatic FA synthesis and not in hepatic FA partitioning. In the second study, subjects consumed a test meal which contained [U13C]fructose to trace the metabolic fate of dietary fructose. It was demonstrated that though there was fast metabolic conversion of fructose into FAs within 2 hours, less than 1% of the ingested fructose was converted to FAs. A much larger proportion of fructose was oxidised into 13CO2 (30.5%). The objective of the third study was to investigate the acute and chronic effect of high fructose consumption on insulin secretion, liver fat content and hepatic de novo lipogenesis (DNL) in subjects. In the crossover acute arm of the study, single dose consumption of the high fructose drink resulted in significantly lower static insulin secretion rate (ISR) in females but not males. This difference in static ISR diminished following prolonged high fructose consumption. It was also found that the daily consumption of either the low or high fructose drink did not change the liver fat content or fasting hepatic DNL in the subjects. Overall, we found notable gender differences in FA metabolism after consumption of low and high fructose meals, the mechanistic details of which can be investigated in future studies.

Raafat al-Ghossain – or ‘Fafo’, as she was known to her father Bassam, mother Saniya and younger sister Kinda – was only 18 when she was killed on 15 April 1986. Her family home in Tripoli was destroyed by a bomb dropped during an American airstrike ordered by Ronald Reagan in response to the bombing of a Berlin nightclub earlier that same year, blamed on the Libyans, in which two American soldiers were killed. Raafat, in her first year at art college in London, was back in Libya visiting her family for the holidays. Just over two months before her death she had written in her diary: ‘My life is changing. I’m slowly, at last, finding myself. It feels great at last to meet my real self. Freedom!!’ On 21 December 1988, Frank Ciulla was travelling home to his wife, Mary Lou, and their three in New Jersey for Christmas. As his flight, Pan Am 103, flew over the Scottish town of Lockerbie a bomb exploded on board the plane, killing all 259 passengers and crew and 11 people on the ground. His body was found eight miles from the main crash site on a farm belonging to Hugh and Mary Connell. The two families subsequently struck up a friendship, culminating in their meeting in Scotland in 1992.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is rapidly becoming one of the leading indications for liver transplantation worldwide. The cellular processes and molecular targets that govern disease development and progression remain to be fully defined and currently there are no licensed treatments. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyses a fundamental step in bile acid synthesis. I have hypothesised that AKR1D1 plays a crucial regulatory role in hepatic metabolic homeostasis. In human hepatoma cell lines, genetic manipulation of AKR1D1 altered primary bile acid biosynthesis and steroid hormone action. Furthermore, gene silencing of AKR1D1 increased hepatocyte triglyceride accumulation through increased de novo lipogenesis and decreased β- oxidation, fueling hepatocyte inflammation as well as increasing glycogen synthesis. I have shown that AKR1D1 has a potent ability to regulate the metabolic phenotype of human hepatocytes suggesting a crucial role in the pathophysiology of NAFLD.